Chemical compounds

ABSTRACT

The present invention provides a compound of a formula (I): 
                         
wherein the variables are defined herein; to a process for preparing such a compound; and to the use of such a compound in the treatment of a chemokine (such as CCR3) or H1 mediated disease state.

This application is a divisional (and claims the benefit of priority under 35 U.S.C. § 120) of U.S. application Ser. No. 10/436,582, filed May 13, 2003, which is a continuation application of U.S. patent application Ser. No. 10/341,027, filed Jan. 13, 2003, now U.S. Pat. No. 6,903,115, which is a divisional of U.S. patent application Ser. No. 09/827,488, filed Apr. 6, 2001 (now issued U.S. Pat. No. 6,525,070), which claims priority from each of UK Application No. 0008626.4, filed Apr. 8, 2000, UK Application No. 0019111.4, filed, Aug. 3, 2000, and Swedish Application No. 0003664-0, filed Oct. 11, 2000. Each of the above applications are hereby incorporated by reference in their entirety.

The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed in WO99/38514, WO99/04794 and WO00/35877.

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rôle in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8–14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C—X—C, or α) and Cys-Cys (C—C, or β) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.

The C—X—C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1–3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, H1, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. H1 antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.

Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, Greiff L et al Allergy (1999) 54(11) 1204–8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].)

The present invention provides a compound of formula (I):

wherein:

-   q, s and t are, independently, 0 or 1; -   n and r are, independently, 0, 1, 2, 3, 4 or 5; -   m and p are, independently, 0, 1 or 2; -   X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; provided that when m and     p are both 1 then X is not CH₂; -   Y is NHR² or OH; -   T is C(O), C(S), S(O)₂ or CH₂; -   R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; -   R² and R⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl     or CO(C₁₋₆ alkyl); -   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or     phthalimide}, CR^(3a)R^(3b)R^(3c), C₂₋₄ alkenyl {optionally     substituted by aryl or heterocyclyl}, C₃₋₇ cycloalkyl {optionally     substituted by C₁₋₄ alkyl, aryl or oxo}, C₃₋₇ cycloalkenyl     {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, aryl,     heterocyclyl, thioaryl or thioheterocyclyl; -   R^(3a) is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₇ cycloalkyl;     R^(3b) is aryl, heterocyclyl, S(O)₂aryl or S(O)₂heterocyclyl; and     R^(3c) is C₁₋₆ alkyl, C₁₋₄ haloalkyl, hydroxy, heterocyclyl(C₁₋₄     alkyl) or aryl; -   wherein, unless stated otherwise, the foregoing aryl and     heterocyclyl moieties are optionally substituted by: halogen, OH,     SH, NO₂, oxo, C₁₋₆ alkyl {itself optionally substituted by halogen,     OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally substituted by     halogen (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl,     S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally substituted     by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself optionally     substituted by C₁₋₄ alkyl or oxo) or NR⁴¹C(O)OCH₂(fluoren-9-yl)},     NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy {itself optionally     substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆ alkyl), CO₂R⁴, NR⁵R⁶     or phenyl (itself optionally substituted by halogen or NO₂)}, C₁₋₆     alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰,     CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³,     NR⁴⁴S(O)₂R⁴⁵, phenyl {itself optionally substituted by halogen, C₁₋₆     alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy (itself optionally     substituted by halogen, OH or pyridinyl), phenyl (itself optionally     substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆     alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl (itself optionally     substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆     alkoxy or C₁₋₆ haloalkoxy)}, heterocyclyl {itself optionally     substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆     alkoxy, C₁₋₆ haloalkoxy, phenyl (itself optionally substituted by     halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆     haloalkoxy) or heterocyclyl (itself optionally substituted by     halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆     haloalkoxy)}, phenoxy {itself optionally substituted by halogen,     C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,     phenyl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy)}, SCN, CN, SO₃H     (or an alkali metal salt thereof), methylenedioxy or     difluoromethylenedioxy; when aryl is phenyl adjacent substituents     may join to form, together with the phenyl ring to which they are     attached, a dihydrophenanthrene moiety; -   d is 0, 1 or 2; -   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹,     R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl, aryl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); -   R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally     substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), C₃₋₆ alkenyl,     aryl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); -   or an N-oxide thereof; or a pharmaceutically acceptable salt     thereof; or a solvate thereof;     provided that: -   when m and p are both 1, n, q and r are all 0, T and X are both     S(O)₂, and R¹ is methoxyphenyl then R³ is not propyl; when m, p, q     and r are all 1, n is 0, Y is NH₂, T is CO and R¹X is (CH₃)₂N then     R³ is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or     1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q     and r are all 0, T is CO, X is NH and R¹ is     3-(4-fluorobenzyl)benzimidazol-2-yl then R³ is not 4-fluorophenyl.

Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate. Another example of an addition salt is sulphate.

The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.

Halogen includes fluorine, chlorine, bromine and iodine.

Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.

Alkenyl group are, for example, vinyl or allyl.

Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl or camphoryl. The cycloalkyl ring is optionally fused to a benzene ring (for example forming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).

Cycloalkenyl is especially monocyclic and is, for example, cyclopentenyl or cyclohexenyl.

Aryl is preferably phenyl or naphthyl.

Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.

In one aspect of the invention heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example, furyl, thienyl, 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, quinoxaline, dihydro-1-benzopyrylium (for example a coumarin or a chromone), piperidine, morpholine, pyrrole, indole, 2,3-dihydroindole, quinoline, thiazole, pyrazole, isoxazole, imidazole, pyridine, benzofuryl, benzimidazole, pyrimidine or dibenzothiophene.

In a further aspect heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), quinolinyl, isoquinolinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.

An N-oxide of a compound of formula (I) is, for example, a 1-oxy-[1,4′]bipiperidinyl-1′-yl compound.

In another aspect the present invention provides a compound of formula (I′):

wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH₂, CO, O, S, S(O), S(O)₂ or NR³⁷; provided that when m and p are both 1 then X is not CH₂; Y is NHR² or OH; T is CO, CS, SO₂ or CH₂; R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R² is hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₆ alkyl); R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl or oxo}, C₃₋₇ cycloalkenyl {optionally substituted by C₁₋₆ alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen, OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl, SO₂R³⁸ or CONR³⁹R⁴⁰), naphthyloxy (itself optionally substituted by halo or C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy (itself optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro, C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹COR¹⁰, CO₂R¹¹, CONR¹²R¹³, COR¹⁴, SO_(d)R¹⁵, SO₂NR⁴²R⁴³, NR⁴⁴SO₂R⁴⁵, phenyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); R¹⁵, R³⁸ and R⁴⁵ are, independently, C₁₋₆ alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both SO₂, and R¹ is methoxyphenyl then R³ is not propyl; when m, p, q and r are all 1, n is 0, Y is NH₂, T is CO and R¹X is (CH₃)₂N then R³ is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R¹ is 3-(4-fluorobenzyl)benzimidazol-2-yl then R³ is not 4-fluorophenyl.

In an further aspect the present invention provides a compound of formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; provided that when m and p are both 1 then X is not CH₂; Y is NHR or OH; T is C(O), C(S), S(O)₂ or CH₂; R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R² and R⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₆ alkyl); R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl or oxo}, C₃₋₇ cycloalkenyl {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen, OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl, S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally substituted by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself optionally substituted by C₁₋₄ alkyl or oxo) or NR⁴¹C(O)OCH₂(fluoren-9-yl)), NR⁴¹ C(O)OCH₂(fluoren-9-yl), C₁₋₄ alkoxy (itself optionally substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆ alkyl), CO₂R⁴, NR⁵R⁶ or phenyl (itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³, NR⁴⁴S(O)₂R⁴⁵, phenyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl) or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both S(O)₂, and R¹ is methoxyphenyl then R³ is not propyl; when m, p, q and r are all 1, n is 0, Y is NH₂, T is CO and R¹X is (CH₃)₂N then R³ is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R¹ is 3-(4-fluorobenzyl)benzimidazol-2-yl then R³ is not 4-fluorophenyl.

In another aspect the variables m and p are such that m+p is 0, 1 or 2 (for example 1 or 2).

In a further aspect n is 0 or 1.

In a still further aspect q and r are both 0.

In another aspect n, q and r are all 0.

In another aspect m, p and t are all 1.

In a further aspect s is 0.

In another aspect s is 1. In a further aspect q is 1. In a still further aspect n+r is equal to more than 1 (for example n+r is equal to 2, 3, 4 or 5).

In another aspect t+m+p is not equal to 3 (for example t+m+p is equal to 2).

In a still further aspect X is O.

In another aspect R¹ is hydrogen, C₁₋₆ alkyl, optionally substituted (as above) aryl or optionally substituted (as above) monocyclic heterocyclyl. In another aspect R¹ is phenyl substituted with one or more of fluorine, chlorine, C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy).

In yet another aspect R¹ is not phenyl substituted by cycloalkyl.

In a further aspect R¹ is phenyl optionally substituted (for example with one, two or three) by halo (especially fluoro or chloro), C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy). In a still farther aspect R¹ is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.

In another aspect R¹ is one of the substituted phenyl groups exemplified in Method F below.

In a further aspect T is C(O), S(O)₂ or CH₂. In a still further aspect T is C(O). In another aspect T is S(O)₂ or CH₂.

In another aspect R³ is aryl or heterocyclyl either of which is optionally substituted as described above.

In a further aspect R³ is unsubstituted phenyl, mono-substituted phenyl or mono-substituted heterocyclyl, the substituents being chosen from those described above.

In a still further aspect R³ is oxo substituted heterocyclyl, said heterocyclyl optionally further substituted with one or more substituents chosen from those described above.

In another aspect R³ is a bicyclic heterocyclyl optionally substituted as described above. Bicyclic heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Bicyclic heterocyclyl is, for example, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl) or a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.

In yet another aspect R³ is: C₁₋₆ alkyl {optionally substituted by CO₂R¹⁶ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by oxo}, phenyl {optionally substituted by: halogen, OH, SH, C₁₋₆ alkyl (itself optionally substituted by naphthyloxy (itself optionally substituted by halo or alkenyl) or NR¹⁷C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself optionally substituted by CO₂R¹⁸, NR¹⁹R²⁰ or phenyl (itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, C₁₋₄ haloalkyl, OCF₃, nitro, C₃₋₇ cycloalkyl, NR²¹R²², NR²³C(O)R²⁴, CO₂R²⁵, C(O)NR²⁶R²⁷, S(O)₂R²⁸, phenyl (itself optionally substituted by NO₂ or alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy, or adjacent substituents may join to form a dihydrophenanthrene moiety}, naphthyl {optionally substituted by NR²⁹R³⁰ or OH}, heterocyclyl {optionally substituted by halo, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or alkyl)), alkoxy, CF₃, thioalkyl, C(O)R³¹, CO₂R³², NR³³C(O)R³⁴, phenoxy, phenyl or nitrogen containing heterocyclyl;

-   R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸,     R²⁹, R³⁰, R³¹, R³², R³³ and R³⁴ are, independently, hydrogen, C₁₋₆     alkyl or phenyl; -   R²⁸ is C₁₋₆ alkyl; or a pharmaceutically acceptable salt thereof.

In another aspect R³ is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R⁴⁶ (wherein k is 0, 1 or 2 (preferably 2); and R⁴⁶ is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂,

In one aspect the variable R³ can be benzo[1,2,3]thiadiazolyl, thiophenyl or phenyl; the phenyl and thiophenyl rings being optionally substituted by: halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R⁴⁶ (wherein k is 0, 1 or 2 (preferably 2); and R⁴⁶ is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

In another aspect the variable R³ can be benzo[1,2,3]thiadiazolyl or phenyl (optionally substituted by: halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itself optionally substituted by S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R⁴⁶ (wherein k is 0, 1 or 2; and R⁴⁶ is C₁₋₄ alkyl or phenyl) or C₁₋₄ haloalkylthio.

In a still further aspect the present invention provides a compound of formula (Ia″):

wherein:

-   T is C(O), C(S), S(O)₂ or CH₂; -   n is 0, 1, 2, 3, 4 or 5; -   m and p are, independently, 0, 1 or 2 (but are especially both 1); -   R⁵⁰ is hydrogen, cyano, S(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ haloalkyl),     halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or phenyl     (optionally substituted by one or two halogen atoms or by one     C(O)NR^(12′)R^(13′), NR^(9′)C(O)R^(10′), S(O)₂R^(15′), S(O)₂NR⁴²R⁴³     or NR⁴⁴S(O)₂R⁴⁵ group); -   R⁵¹ and R⁵² are, independently, hydrogen, halogen, C₁₋₄ alkyl or     C₁₋₄ alkoxy; -   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or     phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl     or oxo}, aryl or heterocyclyl; -   wherein, unless stated otherwise, the foregoing aryl and     heterocyclyl moieties are optionally substituted by: halogen, OH,     SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,     OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or     C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or     C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself     optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself     optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,     C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,     S(O)₂R¹⁵, phenyl (itself optionally substituted by NO₂ or C₁₋₆     alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy,     SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy;     when aryl is phenyl adjacent substituents may join to form, together     with the phenyl ring a dihydrophenanthrene moiety; -   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′),     R¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,     C₁₋₆ alkyl or phenyl; -   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or phenyl;     or a pharmaceutically acceptable salt thereof.

In a further aspect R⁵⁰, R⁵¹ and R⁵² are, independently, hydrogen, halogen, (especially fluoro or chloro), C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy).

In a still further aspect the present invention provides a compound of formula (Ia):

wherein:

-   T is C(O), C(S), S(O)₂ or CH₂; -   n is 0, 1, 2, 3, 4 or 5; -   m and p are, independently, 0, 1 or 2 (but are especially both 1); -   R³⁵ is hydrogen, cyano, S(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ haloalkyl),     halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or phenyl     (optionally substituted by one or two halogen atoms or by one     C(O)NR^(12′)R^(13′), NR^(9′)C(O)R^(10′), S(O)₂R^(15′), S(O)₂NR⁴²R⁴³     or NR⁴⁴S(O)₂R⁴⁵ group); -   R³⁶ is hydrogen, halogen or C₁₋₄ alkyl; -   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or     phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl     or oxo}, aryl or heterocyclyl; -   wherein, unless stated otherwise, the foregoing aryl and     heterocyclyl moieties are optionally substituted by: halogen, OH,     SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,     OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or     C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or     C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself     optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself     optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,     C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,     S(O)₂R¹⁵, phenyl (itself optionally substituted by NO₂ or C₁₋₆     alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy,     SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy;     when aryl is phenyl adjacent substituents may join to form, together     with the phenyl ring a dihydrophenanthrene moiety; -   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′),     R¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,     C₁₋₆ alkyl or phenyl; -   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or phenyl;     or a pharmaceutically acceptable salt thereof

In another aspect the present invention provides a compound of formula (Ia′):

wherein:

-   T is CO, CS, SO₂ or CH₂; -   n is 0, 1, 2, 3, 4 or 5; -   m and p are, independently, 0, 1 or 2 (but are especially both 1); -   R³⁵ is hydrogen, cyano, SO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ haloalkyl),     halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or phenyl     (optionally substituted by one or two halogen atoms or by one     CONR^(12′)R^(13′), NR^(9′)COR^(10′), SO₂R^(15′), SO₂NR⁴²R⁴³ or     NR⁴⁴SO₂R⁴⁵ group); -   R³⁶ is hydrogen, halogen or C₁₋₄ alkyl; -   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or     phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl     or oxo}, aryl or heterocyclyl; -   wherein, unless stated otherwise, the foregoing aryl and     heterocyclyl moieties are optionally substituted by: halogen, OH,     SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,     OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or     C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or     C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself     optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself     optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,     C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹COR¹⁰, CO₂R¹¹, CONR¹²R¹³, COR¹⁴, SO₂R¹⁵,     phenyl (itself optionally substituted by NO₂ or C₁₋₆ alkoxy (itself     optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO₃H     (or an alkali metal salt thereof) or methylenedioxy; when aryl is     phenyl adjacent substituents may join to form, together with the     phenyl ring a dihydrophenanthrene moiety; -   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′),     R¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,     C₁₋₆ alkyl or phenyl; -   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or phenyl;     or a pharmaceutically acceptable salt thereof.

In a further aspect R³ is heterocyclyl (such as thienyl, isoxazolyl or indolyl, or a naphthyridinyl, an imidazopyridinyl or an isoquinolinyl) optionally substituted by oxo, halogen or C₁₋₆ alkyl.

In yet another aspect the present invention provides a compound of formula (Ia) wherein:

-   T is C(O), C(S), S(O)₂ or CH₂; -   n is 0, 1, 2, 3, 4 or 5; -   m and p are, independently, 0, 1 or 2; -   R³⁵ is hydrogen, halogen or phenyl (optionally substituted by one or     two halogen atoms or by one C(O)NR^(12′)R^(13′), NR^(9′C(O)R)     ^(10′), S(O)₂R^(15′), S(O)₂NR⁴²R⁴³ or NR⁴⁴S(O)₂R⁴⁵ group); -   R³⁶ is hydrogen or halogen; -   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or     phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl     or oxo}, aryl or heterocyclyl; -   wherein, unless stated otherwise, the foregoing aryl and     heterocyclyl moieties are optionally substituted by: halogen, OH,     SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,     OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or     C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or     C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself     optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself     optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,     C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,     S(O)₂R¹⁵, phenyl (itself optionally substituted by NO₂ or C₁₋₆     alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy,     SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy;     when aryl is phenyl adjacent substituents may join to form, together     with the phenyl ring a dihydrophenanthrene moiety; -   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′),     R¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,     C₁₋₆ alkyl or aryl; -   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or aryl;     or a pharmaceutically acceptable salt thereof.

In a further aspect R³⁵ and R³⁶ are, independently, hydrogen, halogen, (especially fluoro or chloro), C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy). In another aspect R³⁵ and R³⁶ are both chlorine or both fluorine, especially 3,4 disposed on the phenyl ring to which they are attached.

In a further aspect the present invention provides a compound of formula (Ib):

wherein T, n and R³ are as defined above.

In a still further aspect the present invention provides a compound of formula (Ic):

wherein T, m, p and R³ are as defined above.

In another aspect the present invention provides a compound of formula (Id):

wherein R³ is as defined above.

In yet another aspect the present invention provides a compound of formula (Ie):

wherein R¹, t, s and R³ are as defined above.

In a further aspect the present invention provides a compound of formula (If):

wherein R¹, n, t, s and R³ are as defined above.

In a still further aspect the present invention provides a compound of formula (Ig):

wherein R¹, X and R³ are as defined above.

A compound of formula (I), wherein s is 0, can be prepared by coupling a compound of formula (II):

with a compound of formula (III):

wherein L is a suitable leaving group, and the variables Y and T are optionally protected during the course of the reaction by standard protecting groups known in the art and deprotected in a separate step or during the reaction work-up. For example:

-   when T is carbonyl, L can be OH and the coupling can be carried out     in the presence of a coupling agent (such as     bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, (known as     PYBROP™), oxalyl chloride, thionyl chloride or N,N′-carbonyl     diimidazole, or another coupling agent known to a person skilled in     the art); or, -   when T is sulphonyl, L can be chloro and the coupling can-be carrier     out in the presence of a suitable base (such as potassium carbonate)     in a suitable solvent (such as acetone).

A compound of formula (I), wherein s is 1, R⁴⁷ is hydrogen and T is CO, can be prepared by reacting a compound of formula (II), wherein m and p are both 1, with an aromatic isocyanate of formula with an isocyanate O═C═N—(CH₂)_(n)—(CH₂)_(r)—R³.

A compound of formula (II) can be prepared by deprotecting a compound of formula (IV):

for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane).

A compound of formula (IV), wherein X is O, can be prepared by reacting a compound of formula (V):

with a compound of formula (VI):

in the presence of NaBH(OAc)₃ and acetic acid.

A compound of formula (IV), wherein X is CO or CH₂, can be prepared by oxidising or reducing a compound of formula (VII):

A compound of formula (VII) can be prepared by reacting a compound of formula (VIII):

with a compound of formula (VI) in the presence of NaBH(OAc)₃ and acetic acid. A compound of formula (VIII) can be prepared by reduction of a compound of formula (IX):

A compound of formula (I) wherein X is NR³⁷ can be prepared by reacting a compound of formula (X):

with a compound of formula (XI):

in the presence of NaBH(OAc)₃ and acetic acid. A compound of formula (X) can be prepared by reacting NHR¹R³⁷ with a compound of formula (XII):

in the presence of NaBH(OAc)₃ and acetic acid and then deprotecting the piperidine nitrogen {for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane)}.

Alternatively, a compound of formula (I), wherein s, n, q and r are all 0 and T is CO, can be prepared by reacting a compound of formula (XIII):

with an acid: R³CO₂H. A compound of formula (XIII) can be prepared by deprotecting a compound of formula (XIV):

wherein L* is BOC or a benzyl group. A compound of formula (XIV) can be prepared by performing a fluoride displacement reaction on FR¹ in the presence of compound of formula (XV):

A compound of formula (XV) can be prepared by coupling a compound of formula (XVI) with a compound of formula (XVII):

Alternatively, a compound of formula (I) wherein s, n, q and r are all 0 and T is CO, can be prepared by performing a fluoride displacement reaction on FR¹ in the presence of compound of formula (XVIII):

provided that R⁴⁷ is not hydrogen.

A compound of formula (XVIII) can be prepared by reacting a compound of formula (XIX):

with an appropriate mixed anhydride (such as an anhydride of formula R³C(O)OC(O)(C₁₋₆ alkyl), wherein alkyl is, for example, methyl, ethyl or iso-butyl). A compound of formula (XIX) can be prepared by deprotecting a compound of formula (XV).

Alternatively, a compound of formula (I) can be prepared by reductive ammination of a compound of formula (XX):

with an amine of formula (XXI):

under suitable conditions.

Further compounds of formula (I) can be prepared by adaptation of: the routes described above, methods described in the art or the Examples recited below.

Compounds of formula (V), (VI), (IX), (XI), (XII), (XVI) and (XVII) can be prepared by using or adapting methods described in the art.

In another aspect the present invention provides processes for the preparation of compounds of formula (I) (as defined above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) and (Ig).

The intermediates of formula (II), (IV), (XIII), (XIV) and (XVII) defined herein are novel and these, and processes for their preparation, are provided as further features of the invention.

Examples of compounds of formula (Ib) are listed in Table I below.

TABLE I Compound T n R³ M + H 1 C(O) 0 C₆H₅ 433 2 C(O) 0 3,4-Cl₂—C₆H₃ 501 3 C(O) 0 2,4-Cl₂—C₆H₃ 501 4 C(O) 0 4-CH₃—C₆H₄ 447 5 C(O) 0 4-CH₃O—C₆H₄ 463 6 C(O) 0 4-CF₃—C₆H₄ 501 7 C(O) 0 4-Cl—C₆H₄ 467 8 C(O) 0 4-NO₂—C₆H₄ 478 9 C(O) 0 3,5-Cl₂—C₆H₃ 501 10 C(O) 0 2-F—C₆H₄ 451 11 C(O) 0 4-cyclohexyl-C₆H₄ 515 12 C(O) 0 4-(n-butoxy)-C₆H₄ 505 13 C(O) 0 3-NMe₂—C₆H₄ 476 14 C(O) 0 4-(NHC(O)Me)—C₆H₄ 490 15 C(O) 0 4-NEt₂—C₆H₄ 504 16 C(O) 0 3-CO₂Me—C₆H₄ 491 17 C(O) 0 2-C(O)NH₂—C₆H₄ 18 C(O) 0 4-S(O)₂Me—C₆H₄ 511 19 C(O) 0 2-I—C₆H₄ 559 20 C(O) 0 3-phenoxy-C₆H₄ 525 21 C(O) 0 2-Me—C₆H₄ 447 22 C(O) 0 3-Me—C₆H₄ 447 23 C(O) 0 3-I—C₆H₄ 559 24 C(O) 0 3-NH₂-6-(NHC₆H₅)—C₆H₃ 539 25 C(O) 0 3,5-F₂—C₆H₃ 469 26 C(O) 0 3-NO₂-4-(tert-Bu)-C₆H₃ 534 27 C(O) 0 3-NO₂-5-(CO₂Me)—C₆H₃ 536 28 C(O) 0 2-Me-5-NO₂—C₆H₃ 492 29 C(O) 0 3,5-(tert-Bu)₂-C₆H₃ 545 30 C(O) 0 2-NO₂-5-Me-C₆H₃ 492 31 C(O) 0 2-Br-5-MeO—C₆H₃ 541 32 C(O) 0 3-MeO-4-(CO₂Me)—C₆H₃ 33 C(O) 0 2-(NHC(O)Me)-5-Br—C₆H₃ 568 34 C(O) 0 2-NO₂-5-SCN—C₆H₃ 535 35 C(O) 0 3-MeO-4-Me-C₆H₃ 477 36 C(O) 0 4-CN—C₆H₄ 458 37 C(O) 0 3-CN—C₆H₄ 458 38 C(O) 0 2-phenoxy-4-Br—C₆H₃ 39 C(O) 0 2-NH₂-5-I—C₆H₃ 574 40 C(O) 0 4-F—C₆H₄ 451 41 S(O)₂ 0 2-CF₃O—C₆H₄ 553 42 S(O)₂ 0 3-NO₂-4-Cl—C₆H₃ 548 43 S(O)₂ 0 Camphor-10-yl (alternatively named 7,7- 543 dimethyl-bicyclo[2.2.1]heptan-2-on-1-yl) 44 S(O)₂ 0 n-Pr 435 45 S(O)₂ 0 C₆Me₅ 539 46 S(O)₂ 0 4-(n-Pr)-C₆H₄ 511 47 S(O)₂ 0 Naphth-2-yl 519 48 S(O)₂ 0 2,6-Cl₂—C₆H₃ 537 49 S(O)₂ 0 2,6-F₂—C₆H₃ 505 50 S(O)₂ 0 4-NO₂—C₆H₄ 514 51 S(O)₂ 0 3,4-Cl₂—C₆H₃ 537 52 S(O)₂ 0 2,5-Cl₂—C₆H₃ 53 S(O)₂ 0 5-(NMe₂)-naphth-1-yl 562 54 S(O)₂ 0 2,1,3-benzthiadiazol-4-yl 527 55 S(O)₂ 0 4-Et-C₆H₄ 497 56 S(O)₂ 0 2,5-Cl₂-thien-3-yl 543 57 S(O)₂ 0 3,4-(MeO)₂—C₆H₃ 529 58 S(O)₂ 0 3-CF₃-6-Cl—C₆H₃ 571 59 S(O)₂ 0 5-Cl-thien-2-yl 509 60 S(O)₂ 0 4-Cl—C₆H₄ 503 61 S(O)₂ 0 4-(iso-Pr)-C₆H₄ 511 62 S(O)₂ 0 2-Cl-4-CF₃—C₆H₃ 571 63 S(O)₂ 0 Benzofuraz-4-yl (other name 2,1,3- 511 benzoxadiazol-4-yl) 64 S(O)₂ 0 3-Me-C₆H₄ 483 65 S(O)₂ 0 2,4-F₂—C₆H₃ 505 66 S(O)₂ 0 2-Me-5-F—C₆H₃ 501 67 S(O)₂ 0 4-CF₃O—C₆H₄ 553 68 S(O)₂ 0 iso-Pr 435 70 S(O)₂ 0 4-(CO₂H)—C₆H₄ 513 71 S(O)₂ 0 chromen-2-one-6-yl 537 72 S(O)₂ 0 3,5-Cl₂—C₆H₃ 537 73 S(O)₂ 0 2,3-Cl₂—C₆H₃ 537 74 S(O)₂ 1 4-NO₂—C₆H₄ 75 S(O)₂ 0 3-CF₃—C₆H₄ 537 76 S(O)₂ 0 4-(tert-Bu)-C₆H₄ 525 77 S(O)₂ 0 3-CO₂H-4-OH—C₆H₃ 529 78 S(O)₂ 0 2-NO₂—C₆H₄ 514 79 S(O)₂ 0 2-F—C₆H₄ 487 80 S(O)₂ 0 3-NO₂—C₆H₄ 514 83 S(O)₂ 0 Naphth-1-yl 519 84 S(O)₂ 0 2-MeO-5-Cl—C₆H₃ 533 85 S(O)₂ 0 3-F—C₆H₄ 487 86 S(O)₂ 0 3-Cl-4-(NHC(O)Me)—C₆H₃ 560 87 S(O)₂ 1 C₆H₅ 483 88 S(O)₂ 0 2-NO₂-4-MeO—C₆H₃ 544 89 S(O)₂ 0 2-Me-5-NO₂—C₆H₃ 528 90 S(O)₂ 0 3-CO₂H—C₆H₄ 513 91 S(O)₂ 0 2,4,6-Me₃-C₆H₂ 511 92 S(O)₂ 0 Me 93 S(O)₂ 0 3,4-Cl₂—C₆H₃ 537 94 S(O)₂ 0 4-MeO—C₆H₄ 95 S(O)₂ 0 4-NHC(O)Me—C₆H₄ 526 96 S(O)₂ 0 2-CF₃—C₆H₄ 537 97 S(O)₂ 0 (CH₂)₂CO₂Me 479 98 S(O)₂ 0 4-Me-C₆H₄ 483 99 S(O)₂ 0 4-CF₃—C₆H₄ 537 100 S(O)₂ 0 4-CN—C₆H₄ 494 101 S(O)₂ 0 3-NO₂-4-Me-C₆H₃ 528 102 S(O)₂ 0 1H-2-oxo-quinolin-6-yl 103 S(O)₂ 0 2-(NHCOMe)-4-methylthiazol-5-yl547 104 S(O)₂ 0 Thien-2-yl 475 105 S(O)₂ 0 Quinolin-8-yl 106 S(O)₂ 0 2-OH-3,5-Cl₂—C₆H₂ 553 107 S(O)₂ 0 2-(CO₂Me)—C₆H₄ 527 108 S(O)₂ 0 2,5-(MeO)₂—C₆H₃ 529 109 S(O)₂ 0 phenyl 469 110 S(O)₂ 0 2-Me-4-NO₂—C₆H₃ 528 111 S(O)₂ 0 5-(pyridin-2-yl)thien-2-yl 552 112 S(O)₂ 0 1,3-Me₂-5-Cl-pyrazol-4-yl 521 113 S(O)₂ 0 3,5-Me₂-isoxazol-4-yl 488 114 S(O)₂ 0 2,3,6-Me₃-4-MeO-C₆H 541 115 S(O)₂ 0 1-Me-imidazol-4-yl 473 116 S(O)₂ 0 2-MeO-5-Me-C₆H₃ 513 117 S(O)₂ 0 5-(isoxazol-3-yl)thien-2-yl 542 118 S(O)₂ 0 2-(CO₂Me)thien-3-yl 533 119 S(O)₂ 0 4-(1,1-dimethylprop-1-yl)-C₆H₄ 539 120 S(O)₂ 0 1-(N-phthalimido)-ethyl 566 121 CH₂ 0 4-Me-C₆H₄ 433 122 CH₂ 0 4-(CO₂H)—C₆H₄ 463 123 CH₂ 0 2-(CO₂H)—C₆H₄ 463 124 CH₂ 0 4-(NHC(O)Me)—C₆H₄ 476 125 CH₂ 0 3-OH—C₆H₄ 435 126 CH₂ 0 4-MeO—C₆H₄ 449 127 CH₂ 0 5-Me-fur-2-yl 423 128 CH₂ 0 2,5-F₂—C₆H₃ 455 129 CH₂ 0 5-NO₂-fur-2-yl 130 CH₂ 0 4-NO₂—C₆H₄ 131 CH₂ 0 4-iso-Pr-C₆H₄ 461 132 CH₂ 0 phenyl 419 133 CH₂ 0 2-(SO₃ ⁻Na⁺)—C₆H₄ 498 134 CH₂ 0 4-F—C₆H₄ 437 135 CH₂ 0 2,6-Cl₂—C₆H₃ 487 136 CH₂ 0 3,4-Cl₂—C₆H₃ 487 137 CH₂ 0 2,4-Cl₂—C₆H₃ 138 CH₂ 0 4-(OCH₂CO₂H)—C₆H₄ 493 139 CH₂ 0 Pyrid-2-yl 420 140 CH₂ 0 3-methylthien-2-yl 439 141 CH₂ 0 3-Cl—C₆H₄ 453 142 CH₂ 0 5-methylthien-2-yl 439 143 CH₂ 0 3-OH-4-MeO-C₆H₃ 465 144 CH₂ 0 3-NO₂-4-OH—C₆H₃ 480 145 CH₂ 0 Chromon-3-yl 146 CH₂ 0 1,3-Me₂-5-Cl-pyrazol-4-yl 471 147 CH₂ 0 3,4-F₂—C₆H₃ 455 148 CH₂ 0 4-Cl-pyrazol-3-yl 443 149 C(O) 1 4-S(O)₂Me—C₆H₄ 150 CH₂ 0 2,6-Cl₂-pyridin-4-yl 151 CH₂ 0 5-(4-NO₂—C₆H₄)-fur-2-yl 530 152 CH₂ 0 1-(4-methylbenzyl)-pyrazol-5-yl 153 CH₂ 0 Benzfur-2-yl 459 154 CH₂ 0 2-phenylimidazol-4-yl 485 155 CH₂ 0 5-ethylthien-2-yl 453 156 CH₂ 0 2-Cl-quinolin-3-yl 504 157 CH₂ 0 6-methylpyridin-2-yl 434 158 CH₂ 0 1-acetylindol-3-yl 500 159 CH₂ 0 6-formyl-pyridin-2-yl 448 160 CH₂ 0 Quinolin-3-yl 161 CH₂ 0 5-(CH₂OC(O)CH₃)-fur-2-yl 162 CH₂ 0

529 163 CH₂ 0 Pyridin-4-yl 420 164 CH₂ 0 3-OH-4-NO₂—C₆H₃ 480 165 CH₂ 0 3,5-F₂—C₆H₃ 455 166 CH₂ 0 3-CF₃—C₆H₃ 487 167 CH₂ 0 2-F-6-Cl—C₆H₃ 471 168 CH₂ 0 2-(tert-butyl)S-C₆H₄ 169 CH₂ 0 4-Et-C₆H₄ 447 170 CH₂ 0 3-CO₂H4-OH—C₆H₄ 479 171 CH₂ 0 3-(OCH₂CO₂H)—C₆H₄ 493 172 CH₂ 0 2,3-methylenedioxyphenyl 463 173 CH₂ 0 Thiazol-2-yl 426 174 CH₂ 0 5-ethylfur-2-yl 437 175 CH₂ 0 Quinolin-2-yl 470 176 CH₂ 0 Quinolin-4-yl 470 177 CH₂ 0 4-CH₂CH(CH₃)₂—C₆H₄ 475 178 CH₂ 0 3-MeO-4-OH-5-CO₂H—C₆H₂ 509 179 CH₂ 0 4-bromopyrazol-3-yl 180 CH₂ 0 2-(OCH₂CO₂H)-3-MeO—C₆H₃ 523 181 CH₂ 0 4-(O(CH₂)₃N(CH₃)₂)—C₆H₄ 520 182 CH₂ 0 3-bromothien-2-yl 503 183 CH₂ 0 3-phenoxythien-2-yl 517 184 CH₂ 0 5-methylthio-thien-2-yl 471 185 CH₂ 0 1-methyl-4-bromopyrazol-3-yl 501 186 CH₂ 0 4-I—C₆H₄ 187 CH₂ 0 6,7-Me₂-chromon-3-yl 188 CH₂ 0 2-(OCH₂CO₂H)-5-NO₂—C₆H₄ 538 189 CH₂ 0 2-(2,6-dichloroben.zyloxy)phenyl 593 190 CH₂ 0 1-(4-chlorobenzyl)pyrazol-3-yl 533 191 CH₂ 0 4-iso-propoxy-C₆H₄ 477 192 CH₂ 0 1-methylbenzimidazol-2-yl 473 193 CH₂ 0 3-Me-C₆H₄ 433 194 CH₂ 0 Pyridin-3-yl 420 195 CH₂ 0 2,4-(MeO)₂-pyrimidin-5-yl 196 CH₂ 0 3-Cl-5-CF₃-pyridin-2-yl 522 197 CH₂ 0 2,4-Me₂-C₆H₃ 447 198 CH₂ 0 1-methylindol-3-yl 472 199 CH₂ 0 2-methyl-3-(CO₂Et)-fur-5-yl 200 CH₂ 0 1-Me-4-Cl-pyrazol-3-yl 457 201 C(O) 2 phenyl 461 202 C(O) 1 4-Br—C₆H₄ 525 203 C(O) 1 4-NH₂—C₆H₄ 462 204 C(O) 1 2-Br—C₆H₄ 525 205 C(O) 1 4-F—C₆H₄ 465 206 C(O) 1 2-CF₃—C₆H₄ 207 C(O) 1 3-Me-C₆H₄ 461 208 C(O) 1 2-Me-C₆H₄ 461 209 C(O) 1 3-Cl-4-OH—C₆H₃ 497 210 C(O) 3 9,10-dihydrophenanthren-2-yl 577 211 C(O) 1 2-NO₂—C₆H₄ 492 212 C(O) 1 2-Cl—C₆H₄ 481 213 C(O) 1 4-Cl—C₆H₄ 481 214 C(O) 1 2-benzyloxy-C₆H₄ 553 215 C(O) 2 3,4-(OH)₂—C₆H₃ 493 216 C(O) 1 4-NO₂—C₆H₄ 492 217 C(O) 4 Phenyl 489 218 C(O) 1 3,4-(MeO)₂—C₆H₃ 507 219 C(O) 1 4-EtO—C₆H₄ 491 220 C(O) 1 3-F-4-OH—C₆H₃ 481 221 C(O) 3 Phenyl 475 222 C(O) 1 3,4-methylenedioxyphenyl 491 223 C(O) 3 4-MeO—C₆H₄ 505 224 C(O) 2 4-OH—C₆H₄ 477 225 C(O) 1 4-OH—C₆H₄ 463 226 C(O) 1 4-phenyl-C₆H₄ 523 227 C(O) 1 3,4-Cl₂—C₆H₃ 515 228 C(O) 2 3-OH—C₆H₄ 477 229 C(O) 2 4-Me-C₆H₄ 475 230 C(O) 3 4-NO₂—C₆H₄ 520 231 C(O) 2 3,4-(MeO)₂—C₆H₃ 521 232 C(O) 3 4-Me-C₆H₄ 489 233 C(O) 2 C₆F₅ 551 234 C(O) 3 Dibenzothien-4-yl 581 235 C(O) 1 4-Me-C₆H₄ 461 236 C(O) 2 4-SH—C₆H₄ 237 C(O) 1 4-CF₃O—C₆H₄ 531 238 C(O) 1 4-CH₂Br—C₆H₄ 239 C(O) 3 3,4-(MeO)₂—C₆H₃ 535 240 C(O) 1 4-MeO—C₆H₄ 477 241 C(O) 1 4-(NMe₂)—C₆H₄ 490 242 C(O) 2 4-MeO—C₆H₄ 491 243 C(O) 2 2-MeO—C₆H₄ 491 244 C(O) 1 3,4,5-(MeO)₃—C₆H₂ 537 245 C(O) 2 3,4-methylenedioxyphenyl 505 246 C(O) 2 Dibenzothien-4-yl 247 C(O) 1 3-NH₂—C₆H₄ 462 248 C(O) 1 Naphth-1-yl 497 249 C(O) 1 3-MeO-4-OH—C₆H₃ 493 250 C(O) 1 Naphth-2-yl 251 C(O) I 3-(1-allyl-6-bromonaphth-2-yloxy)CH₂—C₆H₄ 721 252 C(O) 1 4-NO₂—C₆H₄ 253 C(O) 1 3-F-4-MeO—C₆H₃ 495 254 C(O) 4 3-Me-C₆H₄ 503 255 G(O) I 3-OH—C₆H₄ 463 256 C(O) 1 4-benzyloxy-C₆H₄ 553 257 C(O) 1 4-(3-NO₂-C₆H₄—C₆H₄ 568 258 C(O) 1 2,5-(Me)₂—C₆H₃ 475 259 C(O) 1 4-I—C₆H₄ 573 260 C(O) 1 4-(4-(1-Me-2-OH-4-(pyridin-3-yl)-butoxy)- 702 C₆H₄)—C₆H₄ 261 C(O) 1 3-Br—C₆H₄ 525 262 C(O) 2 3-(n-Pr)-C₆H₄ 503 263 C(O) 1 4-(4-NO₂—C₆H₄CH₂O)—C₆H₄ 598 264 C(O) 1 2,5-(OH)₂—C₆H₃ 265 C(O) 1 2-Me-3-NO₂—C₆H₃ 506 266 C(O) 1 4-(CH₂NHCO₂CH₂(fluoren-9-yl))-C₆H₄ 267 C(O) 1 3-OH-4-MeO—C₆H₄ 493 268 C(O) 1 3-F—C₆H₄ 465 269 C(O) 1 2-F—C₆H₄ 465 270 C(O) 1 3,5-(MeO)₂—C₆H₃ 507 271 C(O) 1 3-Cl—C₆H₄ 481 272 C(O) 1 Phenyl 447 273 C(O) I 3,5-Me₂-C₆H₃ 475 274 C(O) 2 3-MeO—C₆H₄ 491 275 C(O) 1 2,4-F₂—C₆H₃ 483 276 C(O) 1 2-MeO—C₆H₄ 477 277 C(O) I 3,4-F₂—C₆H₃ 483 278 C(O) 1 3,5-F₂—C₆H₃ 483 279 C(O) 5 phenyl 503 280 S(O)₂ 0 5-(pyridin-2-yl)-thien-2-yl 281 C(O) 0 3-S(O)₂Me—C₆H₄ 511 282 C(O) 0 3-MeO-4-NH₂—C₆H₃ 283 C(O) 0 3-MeO-4-F—C₆H₃ 481 284 C(O) 0 Benzthiazol-6-yl 490 285 C(O) 0 3-MeO—C₆H₄ 477 286 C(O) 0 3-C₆H₅S(O)—C₆H₄ 557 287 C(O) 0 4-S(O)₂Me—C₆H₄ 511 288 C(O) 0 2,4-Cl₂—C₆H₃ 501 289 C(O) 0 4-NO₂—C₆H₄ 478 290 C(O) 0 3-CN—C₆H₄ 458 291 C(O) 0 4-MeO-C₆H₄ 463 292 C(O) 0 4-CN—C₆H₄ 458 293 C(O) 0 2-S(O)₂Me—C₆H₄ 511 294 C(O) 0 2-Cl-4-S(O)₂Me—C₆H₃ 545 295 C(O) 0 3-(C₆H₅S(O)₂CH₂)-4-NO₂—C₆H₃ 632 296 C(O) 0 2-(C₆H₅S(O)₂CH₂)—C₆H₄ 297 C(O) 0 Benzo[1,2,3]thiadiazol-5-yl 491 298 C(O) 0 4-EtS-C₆H₄ 493 299 C(O) 0 3-CF₃S—C₆H₄ 533 300 C(O) 0 4-CF₃S—C₆H₄ 533 301 C(O) 0 3-CH₃C(O)NH—C₆H₄ 490 302 C(O) 0 3-CH₃-4-NH₂—C₆H₃ 462 303 C(O) 0 Indol-7-yl 472 304 C(O) 0 3-CH₃CH₂O-4-CH₃O—C₆H₃ 507 305 C(O) 0 4-(2,5-dihydropyrrol-1-yl)-C₆H₄ 500 306 C(O) 1 3-Br-pyridin-5-yl 526 307 C(O) 1 1-methyl-imidazol-4-yl 451 308 C(O) 1 5-OH-indol-3-yl 502 309 C(O) 1 Thiophen-3-yl 453 310 C(O) 0 3-CH₃CH₂S(O)₂—C₆H₄ 525 311 C(O) 0 3-CH₃(CH₂)₂S(O)₂—C₆H₄ 539 312 C(O) 0 3-(CH₃)₂CHCH₂S(O)₂—C₆H₄ 553 313 C(O) 0 3,4-(CH₃S(O)₂)₂—C₆H₃ 589 314 C(O) 0 3-CH₃CH₂O-4-NH₂—C₆H₃ 492 315 C(O) 1 Pyridin-4-yl 448 316 C(O) 0 2-CH₃S(O)₂CH₂—C₆H₄ 525 317 C(O) 0 2-NH₂—C₆H₄ 448 318 C(O) 0 1-acetyl-indol-3-yl 319 C(O) 0 Indol-3-yl 320 C(O) 0 3-NH₂(CH₂)₂O—C₆H₄ 321 C(O) 0 3-CH₃NHS(O)₂—C₆H₄ 322 C(O) 0 3-NH₂S(O)₂—C₆H₄ 323 C(O) 0 3-CH₃O(CH₂)₂O—C₆H₄ 324 C(O) 0 3-(CH₃)₃COC(O)NH(CH₂)₂O—C₆H₄ 325 C(O) 0 1,2,3-benzothiadiazol-6-yl 326 C(O) 0 3-HOC(O)CH₂O—C₆H₄ 327 C(O) 0 2-CH₃S(O)₂-3-CN-thiophen-5-yl 542 328 C(O) 0 3-CH₃S(O)₂-4-NH₂—C₆H₃ 526 329 C(O) 0 2-CH₃S(O)₂-3-NH₂C(O)-thiophen-5-yl 560 330 C(O) 0 3-CF₃O—C₆H₄ 501 331 C(O) 0 2-(CH₃)₂CHS(O)₂-3-NH₂-thiophen-4-yl 560 332 C(O) 0 2-CH₃S(O)₂-thiophen-5-yl 517 333 C(O) 0 3-CH₃-5-(4-CH₃-1,2,3-thiadiazol-5-yl)- 536 isoxazol-4-yl 334 C(O) 0 3-Cl-5-CF₃-pyridin-2-yl 536 335 C(O) 1 4-CF₃O—C₆H₄ 531 336 C(O) 0 1H-benzotriazol-5-yl 474 337 C(O) 0 4-CH₃S(O)₂CH₂—C₆H₄ 525 338 C(O) 0 3-CH₃S(O)₂CH₂—C₆H₄ 525 339 C(O) 0 2-CN—C₆H₄ 458 340 C(O) 0 Quinolin-6-yl 484 341 C(O) 0 Quinoxalin-6-yl 485 342 C(O) 0 3-NH₂-4-CH₃S(O)₂-thiophen-2-yl 532 343 C(O) 0

566 344 C(O) 0

345 C(O) 0 3-CF₃O—C₆H₃ 517 346 C(O) 0 2,5-(CH₃O)₂—C₆H₃ 493 347 C(O) 0 1-(CH₃)₂CH-benzotriazol-5-yl 348 C(O) 0

349 C(O) 0 3-HO(CH₂)₂S(O)₂—C₆H₄ 350 C(O) 0 2-HO(CH₂)₂S(O)₂—C₆H₄ 351 C(O) 0 3-cyclopropylCH₂S(O)₂—C₆H₄ 352 C(O) 0 2-CH₃S(O)₂NH—C₆H₄ 526 353 C(O) 0 (CF₃)(MeO)(C₆H₅)C 545 354 C(O) 0 (C₆H₅)₂CH 523 355 C(O) 0 (4-Cl—C₆H₄)(CH₃)₂C 509 356 C(O) 0 (C₆H₅)(cyclohexyl)CH 529 357 C(O) 0 (4-F—C₆H₄)(CH₃)CH 479 358 C(O) 1 3,4-methylenedioxy-C₆H₄ 491 359 C(O) 0 (C₆H₅)(cyclopentyl)CH 515 360 C(O) 0 ((CH₃)(CH₃CH₂)CH)(C₆H₅)CH 503 361 C(O) 0 1-phenyl-cyclopentyl 501 362 C(O) 0 1-(4-Cl—C₆H₄)cyclopentyl 535 363 C(O) 0 1-phenyl-cyclopropyl 473 364 C(O) 0 1-phenyl-cyclohexyl 515 365 C(O) 0 (C₆H₅)(cyclohexyl)C(OH) 545 366 C(O) 0 ((CH₃)₂CH)(C₆H₅)CH 489 367 C(O) 1 pyrid-3-yl 448 368 C(O) 1 pyrid-2-yl 448 369 C(O) 1 5-Br-pyrid-3-yl 526 370 C(O) 1 2,4-(MeO)₂—C₆H₃ 507 371 C(O) 1 4-benzyloxy-phenyl 553 372 C(O) 1 3-benzyloxy-phenyl 553 373 C(O) 1

549 374 C(O) 0 2-EtO-C₆H₄ 491 375 C(O) 0

549 376 C(O) 1 4-n-butoxyphenyl 519 377 C(O) 1 indol-1-yl 486 378 C(O) 1 2-NO₂-phenyl 492 379 C(O) 1 thien-2-yl 453 380 C(O) 1 3-Cl-4-OH-phenyl 497 381 C(O) 1 2-Br-phenyl 525 382 C(O) 1 3-Br-phenyl 525 383 C(O) 1 3,5-F₂-phenyl 483 384 C(O) 1 3-aminophenyl 462 385 C(O) 1 3,4-(OH)₂-phenyl 479 386 C(O) 1 2,5-(MeO)₂-phenyl 507 387 C(O) 1 4-Me-phenyl 461 388 C(O) 0 5-(4-Cl—C₆H₄)-tetrazol-2-yl 549 389 C(O) 1 4-MeS(O)₂-phenyl 525 390 C(O) 1 4-F-phenyl 465 391 C(O) 1 5-Cl-benzo[b]thiophen-3-yl 537 392 C(O) 1 4-CF₃O-phenyl 531 393 C(O) 1 3-Me-5-Cl-benzo[b]thiophen-2-yl 551 394 C(O) 1 2-nitrophenyl 492 395 C(O) I 4-Cl-5-Me-3-NO₂-pyrazol-1-yl 530 396 C(O) 1 2-CF₃-benzimidazol-1-yl 555 397 C(O) 1 2-EtS-benzimidazol-1-yl 547 398 C(O) 1 2-Me-4-(thien-2-yl)-thiazol-5-yl 550 399 C(O) 1 4-Br-3,5-Me₂-pyrazol-1-yl 543 400 C(O) 1 5-Me-3,4-(NO₂)₂-pyrazol-1-yl 541 401 C(O) 1 4-(3-methyl-butoxy)-phenyl 533 402 C(O) 1 2-tert-butylthio-phenyl 535 403 C(O) 1 4-Cl-3,5-Me₂-pyrazol-1-yl 499 404 C(O) 1

535 405 C(O) 1 2,4-(NO₂)₂-imidazol-1-yl 527 406 C(O) 1 3,5-Me₂-pyrazol-1-yl 465 407 C(O) 1 4-n-hexyl-phenyl 531 408 C(O) 0 2-NH₂-pyrid-5-yl 449 409 C(O) 0 Pyrid-2-yl 434 410 C(O) 0 2-EtS-pyrid-3-yl 494 411 C(O) 0 2-OH-quinolin-4-yl 500 412 C(O) 0 2-OH-pyrid-5-yl 450 413 C(O) 0 2,6-(MeO)₂-pyrid-3-yl 494 414 C(O) 0 2-(imidazol-1-yl)-pyrid-5-yl 500 415 C(O) 0 2-CO₂CH₃-pyrid-3-yl 492 416 C(O) 0 2-Me-pyrid-5-yl 448 417 C(O) 0 Quinolin-2-yl 484 418 C(O) 0 6-Me-pyrid-2-yl 448 419 C(O) 0 2-OH-6-Me-pyrid-3-yl 464 420 C(O) 0 8-OH-quinolin-2-yl 500 421 C(O) 1 3-F-phenyl 465 422 C(O) 0 Imidazo[1,2-a]pyrid-2-yl 473 423 C(O) 0 2-methyl-[1,8]naphthyridin-3-yl 499 424 C(O) 0 [1,6]naphthyridin-2-yl 485 425 C(O) 0 2-methyl-[1,6]naphthyridin-3-yl 499 426 C(O) 0 1-methyl-1H-pyrid-2-one-5-yl 464 427 C(O) 0 Quinolin-4-yl 484 428 C(O) 0 Quinolin-6-yl 484 429 C(O) 0 3-(CH₃(CH₂)₂S(O)₂)—C₆H₄ 539 430 C(O) 0 5-((pyrid-2-yl)SCH₂)fur-2-yl 546 431 C(O) 0 2-Me-3-OH-quinolin-4-yl 514 432 C(O) 0 (pyrid-2-yl)CH═CH 460 433 C(O) 0 (2-EtS-pyrid-5-yl)CH═CH 520 434 C(O) 0 1-(5-CF₃-pyrid-2-yl)-piperidin-4-yl 585 435 C(O) 0 2,7-Me₂-imidazo[1,2-a]pyrid-3-yl 501 436 C(O) 0 (5-CF₃-pyrid-2-yl)SO₂CH(CH₃) 594 437 C(O) 1 3-(pyrid-2-yl)pyrazol-1-yl 514 438 C(O) 0 3-NH₂-4-CH₃O—C₆H₃ 478 439 C(O) 0 2,5-(CH₃O)₂—C₆H₃ 493 440 C(O) 0 3-F-4-CH₃—C₆H₃ 465 441 C(O) 0 3-phenyl-5-CH₃-isoxazol-4-yl 514 442 C(O) 0 1-phenyl-5-CH₃-pyrazol-4-yl 513 443 C(O) 0 3-CF₃O—C₆H₄ 517 444 C(O) 0 2-CH₃O-5-Cl—C₆H₃ 497 445 C(O) 0 2-CH₃-3-F—C₆H₃ 465 446 C(O) 0 2-(2-phenyl-thiazol-4-yl)phenyl 592 447 C(O) 0 3,4-methylenedioxyphenyl 477 448 C(O) 0 5-phenyl-oxazol-4-yl 500 449 C(O) 0 1H-indazol-3-yl 473 450 C(O) 0 1-CH₃-indol-3-yl 486 451 C(O) 0 1-iso-propyl-benztriazol-5-yl 516 452 C(O) 0

473 453 C(O) 0 2-CH₃-5-F—C₆H₃ 465 454 C(O) 0 3-CF₃O-4-NH₂—C₆H₃ 532 455 C(O) 0 3-CH₃-5-CF₃-isoxazol-4-yl 506 456 C(O) 0 (1,2,4-triazol-1-yl)C(CH₃)₂ 466 457 C(O) 0 2-phenyl-thiazol-4-yl 516 458 C(O) 0 2-CH₃-4-CF₃-thiazol-5-yl 522 459 C(O) 0

529 460 C(O) 0

558 461 C(O) 0 3-F-4-CF₃—C₆H₃ 519 462 C(O) 0

501 463 C(O) 0 2-CH₃-benzimidazol-5-yl 487 464 C(O) 1

534 465 C(O) 0 3-iso-propoxy-4-CH₃O—C₆H₃ 521 466 C(O) 0

519 467 C(O) 0

534 468 C(O) 0 2-CH₃O-5-F—C₆H₃ 481 469 C(O) 0 3-CH₃CH₂O—C₆H₄ 470 C(O) 0 2-(C₆H₅S(O)CH₂)—C₆H₄ 471 C(O) 0 1H-indol-3-yl 472 472 S(O)₂ 1 2-NO₂—C₆H₄ 528 473 S(O)₂ 0 2-CN—C₆H₄ 494 474 C(O) 0 3-CH₃S(O)₂—C₆H₄ 511 475 C(O) 0 3-S(O)₂NHCH₃—C₆H₄ 526 476 C(O) 0 Benzo[1,2,3]thiadiazol-6-yl 491 477 C(O) 0 3-CH₃O(CH₂)₂O—C₆H₄ 507 478 C(O) 0 3,4-(CH₃S(O)2)₂—C₆H₃ 589 479 C(O) 0 3-CH₃O—C₆H₄ 463 480 C(O) 0 3-CN—C₆H₄ 458 481 C(O) 0 4-F—C₆H₄ 451 482 C(O) 0 3-CH₃O-4-F—C₆H₃ 481 483 C(O) 0 3H-benzothiazol-2-one-6-yl 506 484 C(O) 0 2-CH₃S(O)₂-thien-5-yl 517 485 C(O) 0 3-CH₃-4-NH₂—C₆H₃ 462 486 C(O) 0 Benzothiazol-6-yl 490 487 C(O) 0 1H-5-CH₃S(O)₂-indol-2-yl 550 488 C(O) 0 1H-5-CH₃O-indol-2-yl 502 489 C(O) 0 1H-indol-4-yl 472 490 C(O) 0 1H-Benzimidazol-5-yl 473 491 C(O) 0 3,4-methylenedioxyphenyl 477 492 C(O) 0 1H-5-Cl-indol-2-yl 506 493 C(O) 0 1H-5-OH-indol-2-yl 488 494 C(O) 0

558 495 C(O) 0 3,4-difluoromethylenedioxyphenyl 513 496 C(O) 0 2-(pyrazol-1-yl)-pyridin-5-yl 500 497 C(O) 0 4-CF₃-pyridin-3-yl 502 498 C(O) 0

576 499 C(O) 0

459 500 C(O) 0 3-n-propoxy-pyridin-2-yl 492 501 C(O) 1 2-(2,4-F₂—C₆H₃)thiazol-4-yl 566 502 C(O) 0 1H-indol-2-yl 472 503 C(O) 1 2-phenyl-5-CH₃-thiazol-4-yl 544 504 C(O) 0 2-S(O)₂NH₂-4-Cl—C₆H₃ 546 505 C(O) 0 2-CN—C₆H₄ 458 506 C(O) 0 1H-indol-7-yl 472 507 C(O) 0 1H-5-F-indol-2-yl 490 508 C(O) 0 1H-pyrazol-4-yl 423 509 C(O) 0 1-CH₃-pyrrol-2-yl 436 511 C(O) 0 3-(pyrrol-1-yl)-4-CN-thien-2-yl 529 512 C(O) 0 3-CH₃O-4-NH₂—C₆H₃ 478 513 C(O)C(O) 0 1H-indol-3-yl 500 514 C(O) 0 4-(pyrrol-1-yl)phenyl 498 515 C(O) 0 1-CH₃-indol-2-yl 486 516 C(O) 1 1H-indol-3-yl 486 517 C(O) 1 1H-5-CH₃O-indol-3-yl 516 518 C(O) 0 2-(pyridin-2-yl)-thien-5-yl 516 519 C(O) 0 1H-5-F-indol-2-yl 490 520 C(O) 1 3-CH₃-benzo[b]thiophen-2-yl 517 521 C(O) 1 3,5-(CH₃)₂-4-NO₂-pyrazol-1-yl 510 522 C(O) 0 2-CF₃-[1,6]-naphthyridin-3-yl 553 523 C(O) 0 2-(1-CH₃-5-CF₃-pyrazol-3-yl)-thien-5-yl 587 524 C(O) 0

638 525 C(O) 1 3-Cl—C₆H₄ 481 526 C(O) 1 5-CH₃-3-NO₂-pyrazol-1-yl 496 527 C(O) 1 2-CN—C₆H₄ 472 528 C(O) 0 Quinoxalin-2-yl 485 529 C(O) 0 Pyrazin-2-yl 435 530 C(O) 0

549 531 C(O) 0 1 -tert-butyl-3-CH₃-pyrazol-5-yl 493 532 C(O) 0 2-SH-pyridin-3-yl 466 533 C(O) 0 Quinolin-3-yl 484 534 C(O) 0

543 535 C(O) 0 2-ethoxy-phenyl 477 536 C(O) 1 4-NO₂-imidazol-1-yl 482 537 C(O) 0 4-CH₃O-quinolin-2-yl 514 538 C(O) 0 2-SCH₂CH═CH₂-pyridin-3-yl 506 539 C(O) 0 1-iso-propyl-benztriazol-5-yl 516 540 C(O) 0 [1,8]-naphthyridin-2-yl 485 541 C(O) 1 2-CH₃-4-phenyl-thiazol-5-yl 544 542 C(O) 0 1-CH₃-indol-2-yl 486 543 C(O) 0 2-phenoxy-pyridin-5-yl-CH═CH 552 544 C(O) 1 3,4-Cl₂—C₆H₃ 515 545 C(O) 0 2-S(O)₂CH₃-3-CN-6-CH₃-pyridin-4-yl 551 546 C(O) 0 3H-Benzothiazol-2-one-6-yl 506 547 C(O) 0 2-CH₃O-pyridin-3-yl 464 548 C(O) 0 Isoquinolin-1-yl 484 549 C(O) 1 4-OH—C₆H₄ 463 550 C(O) 0 Quinolin-8-yl 484 551 C(O) 0 2-CN—C₆H₄ 458 552 C(O) 0 2-CF₃-[1,8]-naphthyridin-3-yl 553 553 C(O) 0 2-CO₂CH₃-pyridin-6-yl 492 554 C(O) 0 Isoquinolin-3-yl 484 555 C(O) 0 3-CH₂S(O)₂CH₃—C₆H₄ 525 556 C(O) 0 2-ethoxy-pyridin-3-yl 478 557 C(O) 1

516 558 C(O) 0 2-CH₃O-pyridin-5-yl 464 559 C(O) 0 Indan-1-one-3-yl 487 560 C(O) 1 3-NO₂-[1,2,4]-triazol-1-yl 483 561 C(O) 0 1-(CH₃)₂CH-benzotriazol-5-yl 516 562 C(O) 1 1H-2-CH₃-indol-3-yl 500 563 C(O) 0 3,5-(CH₃)₂-isoxazol-4-yl 452 564 C(O) 0 1,5-(CH₃)₂-pyrazol-4-yl 451 565 C(O) 0 Quinoxalin-6-yl 485 566 C(O) 1 3-NO₂-[1,2,4]triazol-1-yl 483 567 C(O) 0 1H-indol-3-yl-CH═CH 498 568 C(O) 1 4-(pyridin-2-yl)-pyrimidin-2-yl-S 558 569 C(O) 0 3-S(O)₂NH₂—C₆H₄ 512 570 C(O) 1 1H-5-OH-indol-3-yl 502 571 C(O) 0 4-CH₂S(O)₂CH₃—C₆H₄ 525 572 C(O) 0

500 573 C(O) 0 Isoxazol-5-yl 424 574 C(O) 1 1-CH₃-4-NO₂-pyrazol-5-yl 496 575 C(O) 0

645 576 C(O) 0 3-ethoxy-4-amino-phenyl 492 577 C(O) 1 1,4-(CH₃)₂-3-CO₂H-pyrrol-2-yl 508 578 C(O) 0

473 579 C(O) 0

491 580 C(O) 0 2-OH-quinolin-4-yl 500 582 C(O) 0 3-amino-phenyl 448 583 C(O) 0 3-NHS(O)₂CH₃—C₆H₄ 526 584 C(O) 0 3-C(CH₃)₃OC(O)NH(CH₂)₂O—C₆H₄ 592 585 C(O) 0 3-HO₂CCH₂O—C₆H₄ 507 586 C(O) 0 3-H₂N(CH₂)₂O—C₆H₄ 492 587 C(O) 0 2-NHS(O)₂CH₃—C₆H₄ 526 588 C(O) 0 2-S(O)₂CH₂cyclopropyl-C₆H₄ 551 589 C(O) 0 3-S(O)₂N(CH₃)₂—C₆H₄ 540 590 C(O) 0 3-NO₂-5-S(O)₂CH₃—C₆H₃ 556 591 C(O) 0 3-NH₂-5-S(O)₂CH₃—C₆H₃ 526 592 C(O) 0 1-S(O)₂CH₃-indol-3-yl 593 C(O) 0 3-CN-5-S(O)₂CH₃—C₆H₃ 536 594 C(O) 0 1H-5-S(O)₂CH₃-indol-3-yl 550 595 C(O) 0 CH(Phenyl)(CH₂piperazin-1-yl) 545 596 C(O) 1

518 597 C(O) 0 3-S(O)₂NH₂-4-Cl—C₆H₃ 546 598 C(O) 0

474 599 C(O) 0

487 600 C(O) 0

507 601 C(O) 0

487 602 C(O) 0 2-NO₂-5-S(O)₂CH₃—C₆H₃ 603 C(O) 0 2-NH₂-5-S(O)₂CH₃—C₆H₃

Examples of compounds of formula (Ic) are listed in Table II below.

TABLE II Compound m p T R³ 1 1 1 C(O) 3-MeO-4-NH₂—C₆H₃ 2 0 2 C(O) 3-MeO-4-NH₂—C₆H₃ 3 1 1 S(O)₂ 5-(pyridin-2-yl)-thien-2-yl 4 0 1 C(O) 3-MeO-4-NH₂—C₆H₃ 5 1 1 C(O) 3H-benzthiazol-2-one-6-yl 6 1 1 C(O)

7 1 1 C(O) [1,8]naphthyridin-2-yl 8 1 1 C(O)

Examples of compounds of formula (Id) are listed in Table III below.

TABLE III Compound R³ 1 4-F—C₆H₄ 2 Phenyl 3 3,4-F₂—C₆H₃

Examples of compounds of formula (If) are listed in Table IV below.

TABLE IV (If)

Compound R¹ t s n R³ 1 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 2 3-Cl-4-F-C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 3 3-F-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 4 3-CH₃O-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 5 2-CH₃O-4-F—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 6 4-CH₃O—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 7 4-CH₃O—C₆H₄ 0 0 0 3-CH₃S(O)₂—C₆H₄ 8 4-Cl—C₆H₄ 0 0 0 3-CH₃S(O)₂—C₆H₄ 9 3,4-Cl₂—C₆H₃ 0 0 0 3-CH₃S(O)₂—C₆H₄ 10 4-CN—C₆H₄ 0 0 0 3-CH₃S(O)₂—C₆H₄ 11 3,4-F₂C₆H₃ 0 0 0 3-CH₃S(O)₂—C₆H₄ 12 4-F—C₆H₄ 0 0 0 3-CH₃S(O)₂—C₆H₄ 13 4-CH₃C(O)NH—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 14 4-CH₃—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 15 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 16 4-Cl—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 17 4-F—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 18 2,4-Cl₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 19 2-Cl-4-F—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 20 2,4-F₂C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 21 2-F-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 22 2-CH₃-4-F—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 23 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 24 3-F-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 25 2-CH₃O-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 26 2-CH₃O-4-F—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 27 4-CH₃O—C₆H₄ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 28 3-Cl-4-F—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 29 4-CH₃—C₆H₄ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 30 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 31 4-Cl—C₆H₄ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 32 4-F—C₆H₄ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 33 2,4-Cl₂—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 34 2-Cl-4-F—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 35 2,4-F₂C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 36 2-F-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 37 2-CH₃-4-F—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 38 2-CH₃-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 39 3-F-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 40 2-CH₃O-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 41 2-CH₃O-4-F—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 42 4-CH₃O—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl 43 3-Cl-4-F—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 44 4-CH₃—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl 45 3-Cl-4-CH₃—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 46 4-Cl—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl 47 4-F—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl 48 2,4-Cl₂—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 49 2-Cl-4-F—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 50 2,4-F₂—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 51 2-F-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 52 2-CH₃-4-F—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 53 3,4-Cl₂—C₆H₃ 1 1 0 3-CN—C₆H₄ 54 3,4-Cl₂—C₆H₃ 1 1 0 3-CH₃S(O)₂—C₆H₄ 55 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 56 3-Cl-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 57 3-F-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 58 3-CH₃O-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 59 2-CH₃O-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 60 4-CH₃O—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 61 4-CH₃C(O)NH—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 62 4-CH₃—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 63 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 64 4-Cl—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 65 4-F—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 66 2,4-Cl₂—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 67 2-Cl-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 68 2,4-F₂C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 69 2-F-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 70 2-CH₃-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 71 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 72 3-Cl-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 73 3-F-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 74 3-CH₃O-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 75 2-CH₃O-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 76 4-CH₃O-C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 77 4-CH₃C(O)NH—C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 78 4-CH₃—C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 79 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 80 4-Cl—C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 81 4-F—C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 82 2,4-Cl₂—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 83 2-Cl-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 84 2,4-F₂C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 85 2-F-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 86 2-CH₃-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 87 3-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 88 3-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 89 3-CH₃-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 90 3-Cl-4-CH₃—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 91 3-Cl-4-CH₃—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 92 2-CH₃-4-Cl—C₆H₃ 1 0 0 Quinolin-6-yl 93 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-(CH₃O(CH₂)₂O)—C₆H₄ 94 2-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-(CH₃S(O)2)₂—C₆H₃ 95 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O—C₆H₄ 96 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CN—C₆H₄ 97 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-F—C₆H₄ 98 2-CH₃-4-Cl—C₆H₃ 1 0 0 Indol-7-yl 99 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-CH₃S(O)₂-indol-2-yl 100 2-CH₃-4-Cl—C₆H₃ 1 0 0 Benzimidazol-5-yl 101 2-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxy-C₆H₃ 102 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-F-indol-2-yl 103 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-CF₃-thieno[3,2-b]pyridin-6-yl 104 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl 105 3-CH₃-4-Cl—C₆H₃ 1 0 0 Quinolin-6-yl 106 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CN—C₆H₄ 107 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-(CH₃O(CH₂)₂O)—C₆H₄ 108 3-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-(CH₃S(O)₂)₂—C₆H₃ 109 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O—C₆H₄ 110 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CN—C₆H₄ 111 3-CH₃-4-Cl—C₆H₃ 1 0 0 4-F—C₆H₄ 112 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-CH₃S(O)₂-thien-2-yl 113 3-CH₃-4-Cl—C₆H₃ 1 0 0 Indol-7-yl 114 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-CH₃S(O)₂-indol-2-yl 115 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-EtO-4-NH₂—C₆H₃ 116 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-CH₃O-indol-2-yl 117 3-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxy-C₆H₃ 118 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-F-indol-2-yl 119 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-CF₃-thieno[3,2-b]pyridin-6-yl 120 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl 121 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-NH₂-4-MeO-C₆H₃ 122 2-CH₃-4-Cl—C₆H₃ 1 0 0 Pyrazin-2-yl 123 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-phenyl-5-Me-isoxazol-4-yl 124 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O—C₆H₄ 125 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-MeO-5-Cl—C₆H₃ 126 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-Me-3-F—C₆H₃ 127 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-EtO-C₆H₄ 128 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-phenyl-oxazol-4-yl 129 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-F-1H-indol-2-yl 130 2-CH₃-4-Cl—C₆H₃ 1 0 0 2H-isoquinolin-1-one-4-yl 131 2-CH₃-4-Cl—C₆H₃ 1 0 0 3H-benzothiazol-2-one-6-yl 132 2-CH₃-4-Cl—C₆H₃ 1 0 0 Bicyclo[4.2.0]octa-1,3,5-trien-7-yl 133 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-iso-propylbenztriazol-5-yl 134 2-CH₃-4-Cl—C₆H₃ 7 0 0 1-phenylcyclopropyl 135 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-NH₂S(O)₂-4-Cl—C₆H₃ 136 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O-4-NH₂—C₆H₃ 137 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-(pyrrol-1-yl)-4-CN-thien-2-yl 138 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-(CH₃O(CH₂)₂O)-5-NH₂—C₆H₃ 139 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-(1-CH₃-5-CF₃-pyrazol-3-yl)- thien-5-yl 140 2-CH₃-4-Cl—C₆H₃ 1 0 0 (1,2,4-triazol-1-yl)C(CH₃)₂ 141 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-phenyl-thiazol-4-yl 142 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-4-CF₃-thiazol-5-yl 143 2-CH₃-4-Cl—C₆H₃ 1 0 0 [1,8]-naphthyndin-2-yl 144 2-CH₃-4-Cl—C₆H₃ 1 0 0

145 2-CH₃-4-Cl—C₆H₃ 1 0 0

146 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CF₃—C₆H₃ 147 2-CH₃-4-Cl—C₆H₃ 1 0 0

148 2-CH₃-4-Cl—C₆H₃ 1 0 0

149 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-benzimidazol-5-yl 150 2-CH₃-4-Cl—C₆H₃ 1 0 1

151 2-CH₃-4-Cl—C₆H₃ 1 0 0

152 2-CH₃-4-Cl—C₆H₃ 1 0 0 1,5-dimethyl-pyrazol-3-yl 153 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃O-5-F—C₆H₃ 154 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-NH₂-4-CH₃O—C₆H₃ 155 3-CH₃-4-Cl—C₆H₃ 1 0 0 2,5-(CH₃O)₂—C₆H₃ 156 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CH₃—C₆H₃ 157 3-CH₃-4-Cl—C₆H₃ 1 0 0 Pyrazin-2-yl 158 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-phenyl-5-CH₃-isoxazol-4-yl 159 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-phenyl-5-CH₃-pyrazol-4-yl 160 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O—C₆H₄ 161 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃O-5-Cl—C₆H₃ 162 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-3-F—C₆H₃ 163 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃CH₂O—C₆H₄ 164 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-(2-phenyl-thiazol-4-yl)-phenyl 165 3-CH₃-4-Cl—C₆H₃ 1 0 0

166 3-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxyphenyl 167 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-phenyl-oxazol-4-yl 168 3-CH₃-4-Cl—C₆H₃ 1 0 0 Quinoxalin-2-yl 169 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-Pyrazol-4-yl 170 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 171 3-CH₃-4-Cl—C₆H₃ 1 0 0

172 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-iso-propyl-benztriazol-5-yl 173 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-n-propoxy-pyridin-2-yl 174 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-5-F—C₆H₃ 175 3-CH₃-4-Cl—C₆H₃ 1 0 1 (2-S(O)₂NHCH₃—C₆H₄)S 176 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃-5-CF₃-isoxazol-4-yl 177 3-CH₃-4-Cl—C₆H₃ 1 0 1 2-(2,4-F₂C₆H₃)thiazol-4-yl 178 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-(CH₃O(CH₂)₂O)-5-NH₂—C₆H₃ 179 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-phenyl-thiazol-4-yl 180 3-CH₃-4-Cl—C₆H₃ 1 0 0

181 3-CH₃-4-Cl—C₆H₃ 1 0 0

182 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CF₃—C₆H₃ 183 3-CH₃-4-Cl—C₆H₃ 1 0 0

184 3-CH₃-4-Cl—C₆H₃ 1 0 0

185 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-iso-propoxy-C₆H₄ 186 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-benzimidazol-5-yl 187 3-CH₃-4-Cl—C₆H₃ 1 0 1

188 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 189 3-CH₃-4-Cl—C₆H₃ 1 0 0

190 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-tert-butyl-3-CH₃-pyrazol-5-yl 191 3-CH₃-4-Cl—C₆H₃ 1 0 0

192 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃O-5-F—C₆H₃ 193 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-NH₂-4-CH₃O—C₆H₃ 194 3-CH₃-4-Cl—C₆H₃ 1 0 0 2,5-(CH₃O)₂—C₆H₃ 195 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CN—C₆H₄ 196 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃O-4-F—C₆H₃ 197 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-pyrrol-2-yl 198 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂CH₃-4-NH₂—C₆H₃ 199 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-F-indol-2-yl 200 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-CH₃O-indol-3-yl 201 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CH₃—C₆H₃ 202 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-phenyl-5-CH₃-pyrazol-4-yl 203 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-(2-phenyl-thiazol-4-yl)-phenyl 204 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-F-indol-2-yl 205 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O-4-NH₂—C₆H₃ 206 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-iso-propoxy-4-CH₃O—C₆H₃ 207 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-CH₃O-indol-2-yl 208 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-indol-4-yl 209 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-CF₃-pyridin-3-yl 210 2-CH₃-4-Cl—C₆H₃ 1 0 0

211 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 212 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-iso-propoxy-4-CH₃O—C₆H₃ 213 3-CH₃-4-Cl—C₆H₃ 1 0 1 1H-indol-3-yl 214 2-CH₃-4-Cl—C₆H₃ 1 0 0

215 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 216 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂NH₂-4-Cl—C₆H₃ 217 3-CH₃-4-Cl—C₆H₃ 1 0 0

218 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-(pyrrol-1-yl)-3-CN-thien-2-yl 219 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-(pyrrol-1-yl)phenyl 220 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-indazo-3-yl 221 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O—NH₂—C₆H₃ 222 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 223 3-CH₃-4-Cl—C₆H₃ 1 0 0

224 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-S(O)₂CH₃—C₆H₄ 225 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-(1-CH₃-5-CF₃-pyrazol-3-yl)- thien-5-yl 226 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-5-F—C₆H₃ 227 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-CH₂S(O)₂CH₃—C₆H₄ 228 2-CH₃-4-Cl—C₆H₃ 1 0 0 Quinoxalin-2-yl 229 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-Cl-indol-2-yl 230 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₂S(O)₂CH₃—C₆H₄ 231 2-CH₃-4-Cl—C₆H₃ 1 0 1 2-(2,4-F₂-C₆H₃)thiazol-4-yl 232 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂NH₂—C₆H₄ 233 2-CH₃-4-Cl—C₆H₃ 1 0 1 1H-indol-3-yl 234 3-CH₃-4-Cl—C₆H₃ 1 0 0 4-S(O)₂CH₃—C₆H₄ 235 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 236 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃-5-CF₃-isoxazol-4-yl 237 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 238 4-S(O)₂CH₃—C₆H₄ 1 0 0 3,4-Cl₂—C₆H₃ 239 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 240 3-CH₃-4-Cl—C₆H₃ 1 0 0 [1,8]-naphthyridin-2-yl 241 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂CH₃—C61-i4 242 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-OH—C₆H₄ 243 3-CH₃-4-Cl—C₆H₃ 1 0 0 3H-Benzthiazol-2-one-6-yl 244 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-n-propoxy-pyridin-2-yl 245 2-CH₃-4-Cl—C₆H₃ 1 0 0 3H-Benzthiazol-2-one-6-yl 246 2-CH₃-4-Cl—C₆H₃ 1 0 0 Isoxazol-5-yl 247 2-CH₃-4-Cl—C₆H₃ 1 0 0 2,5-(CH₃O)₂—C₆H₃ 248 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-pyrazol-4-yl 249 3-CH₃-4-Cl—C₆H₃ 1 0 0 Benzothiazol-6-yl 250 2-CH₃-4-Cl—C₆H₃ 1 0 0 3,5-(CH₃)₂-isoxazol-4-yl 251 3-CH₃-4-Cl—C₆H₃ 1 0 0 4-CF₃-pyridin-3-yl 252 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-indol-4-yl 253 3-CH₃-4-Cl—C₆H₃ 1 0 0 1,5-(CH₃)₂-pyrazol-3-yl 254 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-indazol-3-yl 255 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂NH₂—C₆H₄ 256 2-CH₃-4-Cl—C₆H₃ 1 0 1 4-S(O)₂CH₃—C₆H₄ 257 2-CH₃-4-Cl—C₆H₃ 1 0 0 Benzthiazol-6-yl 258 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-OH-indol-2-yl 259 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₂S(O)₂CH₃—C₆H₄ 260 2-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxyphenyl 261 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-pyrrol-2-yl 262 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃-4-NH₂—C₆H₃ 263 3-CH₃-4-Cl—C₆H₃ 1 0 0 Isoxazol-5-yl 264 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-OH—C₆H₄ 265 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-OH-indol-3-yl 266 3-CH₃-4-Cl—C₆H₃ 1 0 0

267 2-CH₃-4-Cl—C₆H₃ 1 0 0

268 2-CH₃-4-Cl—C₆H₃ 1 0 0

269 3-CH₃-4-Cl—C₆H₃ 1 0 0

270 3-CH₃-4-Cl—C₆H₃ 1 0 0

271 2-CH₃O-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 272 2,6-(CH₃)₂-4-Cl—C₆H₂ 1 0 0 3-CH₃S(O)₂—C₆H₄ 273 2,3-Cl₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 274 2,5-Cl₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 275 2-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 276 2-Cl-5-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 277 2-CH₃-4-C(O)CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 278 2-(morpholin-4-yl)-C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 279 3-CH₃CH₂-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 280 Naphth-7-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 281 2-tert-butyl-C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 282 Indan-5-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 283 2-cyclohexyl-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 284 2-C(O)NH₂-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 285 2-isoxazol-5-yl-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 286 2-CH₃-5-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 287 phenyl 1 0 0 3-CH₃S(O)₂—C₆H₄ 288 2,4-Cl₂-6-CH₃—C₆H₂ 1 0 0 3-CH₃S(O)₂—C₆H₄ 289 3-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 290 2-CN-4-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 291 2-CN-4-CF₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 292 2-CH₃-pyridin-6-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 293 Pyrimidin-2-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 294 2-Cl-4-F—C₆H₃ 1 0 0 2-Cl-4-CH₃S(O)₂—C₆H₃ 295 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 296 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-Cl-4-CH₃S(O)₂—C₆H₃ 297 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂NH₂-4-Cl—C₆H₃ 298 2-CH₃-4-Cl—C₆H₃ 1 0 0

299 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 3-S(O)₂CH₃—C₆H₄ 300 2-ethyl-4-F—C₆H₃ 1 0 0 3-S(O)₂CH₃—C₆H₄ 301 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-S(O)₂CH₃-indol-2-yl 302 2-CH₃-4-Cl—C₆H₃ 1 0 1

303 3-CH₃-4-Cl—C₆H₃ 1 0 1

304 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0

305 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl 306 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 2-S(O)₂CH₃-thien-5-yl 307 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 4-S(O)₂CH₃—C₆H₄ 308 5-CF₃-pyridin-2-yl 1 0 0 3-S(O)₂CH₃—C₆H₄ 309 3,4-Cl₂—C₆H₃ 1 1 0 phenyl 310 3,4-Cl₂—C₆H₃ 1 1 0 4-OCH₃—C₆H₄ 311 3,4-Cl₂—C₆H₃ 1 1 0 4-F—C₆H₄ 312 3,4-Cl₂—C₆H₃ 1 1 0 3-SCH₃—C₆H₄ 313 3,4-Cl₂—C₆H₃ 1 1 1 phenyl 314 3,4-Cl₂—C₆H₃ 1 1 1 4-OCH₃—C₆H₄ 315 3,4-Cl₂—C₆H₃ 1 1 1 4-F—C₆H₄

Examples of compounds of formula (Ig) are listed in Table V below.

TABLE V R¹ X R³ 1 3,4-Cl₂—C₆H₃ CH₂ 3-S(O)₂CH₃—C₆H₄ 2 3,4-Cl₂—C₆H₃ NH 3-S(O)₂CH₃—C₆H₄ 3 3,4-Cl₂—C₆H₃ C(O) 3-S(O)₂CH₃—C₆H₄ 4 3,4-Cl₂—C₆H₃ S(O)₂ 4-S(O)₂CH₃—C₆H₄ 5 3,4-Cl₂—C₆H₃ S(O)₂ C₆H₅

The compounds of formula (I):

wherein:

-   q, s and t are, independently, 0 or 1; -   n and r are, independently, 0, 1, 2, 3, 4 or 5; -   m and p are, independently, 0, 1 or 2; -   X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; -   Y is NHR² or OH; -   T is C(O), C(S), S(O)₂ or CH₂; -   R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; -   R² and R⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl     or CO(C₁₋₆ alkyl); -   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or     phthalimide}, CR^(3a)R^(3b)R^(3c), C₂₋₄ alkenyl {optionally     substituted by aryl or heterocyclyl}, C₃₋₇ cycloalkyl {optionally     substituted by C₁₋₄ alkyl, aryl or oxo}, C₃₋₇ cycloalkenyl     {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, aryl,     heterocyclyl, thioaryl or thioheterocyclyl; -   R^(3a) is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₇ cycloalkyl;     R^(3b) is aryl, heterocyclyl, S(O)₂aryl or S(O)₂heterocyclyl; and     R^(3c) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, hydroxy, heterocyclyl(C₁₋₄     alkyl) or aryl; -   wherein, unless stated otherwise, the foregoing aryl and     heterocyclyl moieties are optionally substituted by: halogen, OH,     SH, NO₂, oxo, C₁₋₆ alkyl {itself optionally substituted by halogen,     OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally substituted by     halogen (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl,     S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally substituted     by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself optionally     substituted by C₁₋₄ alkyl or oxo) or NR⁴¹C(O)OCH₂(fluoren-9-yl)},     NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy {itself optionally     substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆ alkyl), CO₂R⁴, NR⁵R⁶     or phenyl (itself optionally substituted by halogen or N0₂)}, C₁₋₆     alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰,     CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³,     NR⁴⁴S(O)₂R⁴⁵, phenyl {itself optionally substituted by halogen, C₁₋₆     alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy (itself optionally     substituted by halogen, OH or pyridinyl), phenyl (itself optionally     substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆     alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl (itself optionally     substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆     alkoxy or C₁₋₆ haloalkoxy)}, heterocyclyl {itself optionally     substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆     alkoxy, C₁₋₆ haloalkoxy, phenyl (itself optionally substituted by     halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆     haloalkoxy) or heterocyclyl (itself optionally substituted by     halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆     haloalkoxy)}, phenoxy {itself optionally substituted by halogen,     C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,     phenyl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy)}, SCN, CN, SO₃H     (or an alkali metal salt thereof), methylenedioxy or     difluoromethylenedioxy; when aryl is phenyl adjacent substituents     may join to form, together with the phenyl ring to which they are     attached, a dihydrophenanthrene moiety; -   d is 0, 1 or 2; -   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹,     R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl, aryl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); -   R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally     substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), C₃₋₆ alkenyl,     aryl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl     (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆     haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); -   or an N-oxide thereof; or a pharmaceutically acceptable salt     thereof; or a solvate thereof; have activity as pharmaceuticals, in     particular as modulators of chemokine receptor (especially CCR3)     activity, and may be used in the treatment of autoimmune,     inflammatory, proliferative or hyperproliferative diseases, or     immunologically-mediated diseases (including rejection of     transplanted organs or tissues and Acquired Immunodeficiency     Syndrome (AIDS)).

In one aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways     including: chronic obstructive pulmonary disease (COPD) (such as     irreversible COPD); asthma {such as bronchial, allergic, intrinsic,     extrinsic or dust asthma, particularly chronic or inveterate asthma     (for example late asthma or airways hyper-responsiveness)};     bronchitis {such as eosinophilic bronchitis}; acute, allergic,     atrophic rhinitis or chronic rhinitis including rhinitis caseosa,     hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or     rhinitis medicamentosa; membranous rhinitis including croupous,     fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;     seasonal rhinitis including rhinitis nervosa (hay fever) or     vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;     nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,     antitussive activity, treatment of chronic cough associated with     inflammatory conditions of the airways or iatrogenic induced cough; -   (2) (bone and joints) arthrides including rheumatic, infectious,     autoimmune, seronegative spondyloarthropathies (such as ankylosing     spondylitis, psoriatic arthritis or Reiter's disease), Behcet's     disease, Sjogren's syndrome or systemic sclerosis; -   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis     or other eczmatous dermitides, seborrhoetic dermatitis, Lichen     planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,     urticaria, angiodermas, vasculitides erythemas, cutaneous     eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; -   (4) (gastrointestinal tract) Coeliac disease, proctitis,     eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,     ulcerative colitis, irritable bowel disease or food-related     allergies which have effects remote from the gut (for example     migraine, rhinitis or eczema); -   (5) (Allograft rejection) acute and chronic following, for example,     transplantation of kidney, heart, liver, lung, bone marrow, skin or     cornea; or chronic graft versus host disease; and/or -   (6) (other tissues or diseases) Alzheimer's disease, multiple     sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome     (AIDS), Lupus disorders (such as lupus erythematosus or systemic     lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,     type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper     IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal     disease, Sezary syndrome, idiopathic thrombocytopenia pupura or     disorders of the menstrual cycle.

In another aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways     including: chronic obstructive pulmonary disease (COPD) (such as     irreversible COPD); asthma {such as bronchial, allergic, intrinsic,     extrinsic or dust asthma, particularly chronic or inveterate asthma     (for example late asthma or airways hyper-responsiveness)};     bronchitis {such as eosinophilic bronchitis}; acute, allergic,     atrophic rhinitis or chronic rhinitis including rhinitis caseosa,     hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or     rhinitis medicamentosa; membranous rhinitis including croupous,     fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;     seasonal rhinitis including rhinitis nervosa (hay fever) or     vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;     nasal polyposis; fibroid lung or idiopathic interstitial pneumonia; -   (2) (bone and joints) artides including rheumatic, infectious,     autoimmune, seronegative spondyloarthropathies (such as ankylosing     spondylitis, psoriatic arthritis or Reiter's disease), Behcet's     disease, Sjogren's syndrome or systemic sclerosis; -   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis     or other eczmatous dermitides, seborrhoetic dermatitis, Lichen     planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,     urticaria, angiodermas, vasculitides erythemas, cutaneous     eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; -   (4) (gastrointestinal tract) Coeliac disease, proctitis,     eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,     ulcerative colitis, irritable bowel disease or food-related     allergies which have effects remote from the gut (for example     migraine, rhinitis or eczema); -   (5) (Allograft rejection) acute and chronic following, for example,     transplantation of kidney, heart, liver, lung, bone marrow, skin or     cornea; or chronic graft versus host disease; and/or -   (6) (other tissues or diseases) Alzheimer's disease, multiple     sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome     (AIDS), Lupus disorders (such as lupus erythematosus or systemic     lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,     type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper     IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal     disease, sezary syndrome, idiopathic thrombocytopenia pupura or     disorders of the menstrual cycle.

In a further aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways     including: chronic obstructive pulmonary disease (COPD) (such as     irreversible COPD); asthma {such as bronchial, allergic, intrinsic,     extrinsic or dust asthma, particularly chronic or inveterate asthma     (for example late asthma or airways hyper-responsiveness)};     bronchitis {such as eosinophilic bronchitis}; acute, allergic,     atrophic rhinitis or chronic rhinitis including rhinitis caseosa,     hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or     rhinitis medicamentosa; membranous rhinitis including croupous,     fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;     seasonal rhinitis including rhinitis nervosa (hay fever) or     vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;     nasal polyposis; fibroid lung or idiopathic interstitial pneumonia; -   (2) (bone and joints) arthrides including rheumatic, infectious,     autoimmune, seronegative spondyloarthropathies (such as ankylosing     spondylitis, psoriatic arthritis or Reiter's disease), Behcet's     disease, Sjogren's syndrome or systemic sclerosis; -   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis     or other eczmatous dermitides, seborrhoetic dermatitis, Lichen     planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,     urticaria, angiodermas, vasculitides erythemas, cutaneous     eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; -   (4) (gastrointestinal tract) Coeliac disease, proctitis,     eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,     ulcerative colitis, irritable bowel disease or food-related     allergies which have effects remote from the gut (for example     migraine, rhinitis or eczema); -   (5) (Allograft rejection) acute and chronic following, for example,     transplantation of kidney, heart, liver, lung, bone marrow, skin or     cornea; or chronic graft versus host disease; and/or -   (6) (other tissues or diseases) Alzheimer's disease, multiple     sclerosis, atherosclerosis, Lupus disorders (such as lupus     erythematosus or systemic lupus), erythematosus, Hashimoto's     thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome,     eosinophilia fascitis, hyper IgE syndrome, leprosy (such as     lepromatous leprosy), Peridontal disease, sezary syndrome,     idiopathic thrombocytopenia pupura or disorders of the menstrual     cycle.

The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, are also H1 antagonists and may be used in the treatment of allergic disorders.

The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).

Thus, in a further aspect the present invention provides a compound of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, which is both a modulator of chemokine receptor (especially CCR3) activity and an H1 antagonist.

According to a further feature of the invention there is provided a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a pharmaceutically acceptable salt thereof or a solvate thereof.

According to another feature of the present invention there is provided a method for antagonising H1 in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof

The invention also provides a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.

In another aspect the invention provides the use of a compound of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).

In a further aspect the present invention provides the use of a compound of the formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; Y is NHR² or OH; T is C(O), C(S), S(O)₂ or CH₂; R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R² and R⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₆ alkyl); R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl or oxo}, C₃₋₇ cycloalkenyl {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen, OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl, S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally. substituted by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself optionally substituted by C₁₋₄ alkyl or oxo) or NR⁴¹C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy (itself optionally substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆ alkyl), CO₂R⁴, NR⁵R⁶ or phenyl (itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³, NR⁴⁴S(O)₂R⁴⁵, phenyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl) or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).

In another aspect the present invention provides the use of a compound of the formula (I′):

wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH₂, CO, O, S, S(O), S(O)₂ or NR³⁷; Y is NHR² or OH; T is CO, CS, SO₂ or CH₂; R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R² is hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₆ alkyl); R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl or oxo}, C₃₋₇ cycloalkenyl {optionally substituted by C₁₋₆ alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen, OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl, SO₂R³⁸ or CONR³⁹R⁴⁰), naphthyloxy (itself optionally substituted by halo or C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy (itself optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro, C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹COR¹⁰, CO₂R¹¹, CONR¹²R¹³, COR¹⁴, SO_(d)R¹⁵, SO₂NR⁴²R⁴³, NR⁴⁴SO₂R⁴⁵, phenyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); R¹⁵, R³⁸ and R⁴⁵ are, independently, C₁₋₆ alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man).

The invention further provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:

-   (1) (the respiratory tract) obstructive diseases of airways     including: chronic obstructive pulmonary disease (COPD) (such as     irreversible COPD); asthma {such as bronchial, allergic, intrinsic,     extrinsic or dust asthma, particularly chronic or inveterate asthma     (for example late asthma or airways hyper-responsiveness)};     bronchitis {such as eosinophilic bronchitis}; acute, allergic,     atrophic rhinitis or chronic rhinitis including rhinitis caseosa,     hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or     rhinitis medicamentosa; membranous rhinitis including croupous,     fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;     seasonal rhinitis including rhinitis nervosa (hay fever) or     vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;     nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,     antitussive activity, treatment of chronic cough associated with     inflammatory conditions of the airways or iatrogenic induced cough; -   (2) (bone and joints) arthrides including rheumatic, infectious,     autoimnmune, seronegative spondyloarthropathies (such as ankylosing     spondylitis, psoriatic arthritis or Reiter's disease), Behcet's     disease, Sjogren's syndrome or systemic sclerosis; -   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis     or other eczmatous dermitides, seborrhoetic dermatitis, Lichen     planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,     urticaria, angiodermas, vasculitides erythemas, cutaneous     eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; -   (4) (gastrointestinal tract) Coeliac disease, proctitis,     eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,     ulcerative colitis, irritable bowel disease or food-related     allergies which have effects remote from the gut (for example     migraine, rhinitis or eczema); -   (5) (Allograft rejection) acute and chronic following, for example,     transplantation of kidney, heart, liver, lung, bone marrow, skin or     cornea; or chronic graft versus host disease; and/or -   (6) (other tissues or diseases) Alzheimer's disease, multiple     sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome     (AIDS), Lupus disorders (such as lupus erythematosus or systemic     lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,     type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper     IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal     disease, sezary syndrome, idiopathic thrombocytopenia pupura or     disorders of the menstrual cycle;     in a warm blooded animal, such as man.

In a further aspect a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}.

In a still further aspect a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.

The invention also provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection).

The present invention also provides a the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.

The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) or an H1 mediated disease state (such as an allergic disorder) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.

The present invention also provides a method of treating a sign and/or symptom of a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising H1, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of the compound, preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically-acceptable salt thereof (hereafter Compound X), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

(b) Tablet II mg/tablet Compound X 50 Lactose Ph. Eur. 229 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

(c) Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur. 92 Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur. 389 Croscarmellose sodium 100 Magnesium stearate 1.0 (e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)–(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

-   (i) when given, ¹H NMR data is quoted and is in the form of delta     values for major diagnostic protons, given in parts per million     (ppm) relative to tetramethylsilane (TMS) as an internal standard,     determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6     (CD₃SOCD₃) or CDCl₃ as the solvent unless otherwise stated; -   (ii) mass spectra (MS) were run with an electron energy of 70     electron volts in the chemical ionisation (CI) mode using a direct     exposure probe; where indicated ionisation was effected by electron     impact (EI) or fast atom bombardment (FAB); where values for m/z are     given, generally only ions which indicate the parent mass are     reported, and unless otherwise stated the mass ion quoted is the     positive mass ion −(M+H)⁺; -   (iii) the title and sub-titled compounds of the examples and methods     were named using the AUTONOM program from Beilstein     informationssysteme GmbH; -   (iv) unless stated otherwise, reverse phase HPLC was conducted using     a Symmetry, NovaPak or Ex-Terra reverse phase silica column; and -   (v) the following abbreviations are used:

RPHPLC reverse phase HPLC THF tetrahydrofuran RT room temperature DCM dichloromethane DEAD diethyl-azodicarboxylate TFA trifluoroacetic acid NMP N-methylpyrrolidone m.pt. melting point CDI N,N′-carbonyl diimidazole DMSO dimethylsulfoxide MTBE tert-butyl methyl ether Ac Acetate DMF N,N-dimethylformamide aq aqueous Boc or BOC tert-butoxycarbonyl IPA iso-propyl alcohol HPLC high pressure liquid equiv. equivalents chromatography PYBROP ™ bromo-tris-pyrrolidino- phosphonium hexafluorophosphate

EXAMPLE 1

This Example illustrates the preparation of 4-(3,4-dichlorophenoxy)piperidine.

Step a: tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate

Diethyl azodicarboxylate (41.0 ml) was added to a solution of triphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After 15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15 minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) in tetrahydrofuran (400 ml) was added dropwise over 30 min. The solution was stirred at room temperature for 16 hours and concentrated to a small volume. Purification by chromatography (ethyl acetate:iso-hexane 95:5) gave the sub-title compound as an oil (61.3 g).

MS: APCI(+ve): 246 (M−BOC+2H)

Step b: 4-(3,4-Dichlorophenoxy)piperidine

The product from Step a was dissolved in dichloromethane (600 ml) and trifluoroacetic acid (300 ml) was added. After 24 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (36.6 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the title compound as a gum (25 g).

¹H NMR: δ(CDCl₃) 1.77 (1H, br s), 2.05–2.26 (4H, m), 3.20–3.49 (4H, m), 4.61 (1H, s), 6.69–7.52 (3H, m).

EXAMPLE 2

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate (acetate salt of Compound 281 in Table I).

Step a: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in 1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g) followed by NaBH(OAc)₃ (1.81 g) and acetic acid (0.37 g). After 18 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO₄ and concentrated. Purification by silica chromatography (dichloromethane:methanol 92:8) gave the sub-title product (1.97 g).

MS: APCI(+ve): 429 (M+H)

Step b: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine

The product of Step a was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (15 ml) was added. After 4 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the trifluoroacetate salt of the sub-titled product as a solid (1.15 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the sub-title compound as a solid (0.68 g).

¹H NMR: δ(CDCl₃) 1.38–1.51 (2H, m), 1.74–2.02 (6H, m), 2.38–2.50 (3H, m), 2.56–2.61 (2H, m), 2.79–2.86 (2H, m), 3.14–3.18 (2H, m), 4.22–4.28 (1H, m), 6.73–7.32 (3H, m).

Step c: [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate

The product of Step b (0.15 g) was dissolved in THF (4 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.235 g), 3-methylsulphonylbenzoic acid (0.091 g) and N,N-di-iso-propylethylamine (0.238 ml) were added. After 18 hours at room temperature ethyl acetate and aqueous NaHCO₃ solution were added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na₂SO₄ and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH₄OAc_(aq) (0.1%) to 95% MeCN//NH₄OAc_(aq) (0.1%)) gave the title compound (0.095 g).

¹H NMR: δ(DMSO-D6) 1.44–1.94 (8H, m), 2.37–2.77 (5H, m), 3.07–3.55 (6H, m), 4.40 (1H, m), 4.50–4.53 (1H, m), 6.96–8.02 (7H, m).

Melting point: 60–61° C. becomes a gum.

Melting point of free base: 154° C.

EXAMPLE 3

This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone acetate (Compound 282 of Table I).

The compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.016 g).

¹H NMR: δ(DMSO-D6) 1.32–2.01 (8H, m), 2.28–2.88 (5H, m), 3.32 (4H, br s), 3.77 (3H, s), 4.13 (2H, br s), 4.39–4.44 (1H, m), 6.59–7.50 (6H, m).

Melting point: 171° C. becomes a gum.

EXAMPLE 4

This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone (Compound 4 of Table II).

Step a: tert-Butyl 4-(3,4-difluorophenoxy)-1-piperidinecarboxylate

This compound was prepared according to the method of Example 1 Step a using 3,4-difluorophenol to afford the compound as an oil (5.4 g).

MS: ESI(+ve): 213 (M−BOC+H)

Step b: 4-(3,4-Difluorophenoxy)piperidine

This compound was prepared according to the method of Example 1 Step b to afford the compound as a pale yellow oil (3 g).

MS: ESI(+ve): 214 (+H)

Step c: 3-[4-(3,4-Difluoro-phenoxy)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

The product of Step b (0.5 g) was dissolved in 1,2-dichloroethane (7 ml). tert-Butyl 3-oxo-1-pyrrolidinecarboxylate (0.43 g) was added followed by NaBH(OAc)₃ (0.7 g) and acetic acid (0.08 g). After 24 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO₄ and concentrated. Purification by silica chromatography (100% ethyl acetate) gave the sub-title product (0.79 g).

MS: ESI(+ve): 383 (M+H)

Step d: 3,4-Difluorophenyl 1-(3-pyrrolidinyl)-4-piperidinyl ether

The product of Step c was dissolved in dioxane (10 ml) and HCl (6N) (10 ml) was added and the reaction stirred for 3 hrs. Organic solvent was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na₂SO₄ and concentrated to give the sub-title product as an oil (0.54 g).

¹H NMR: δ(CDCl₃) 1.60–2.39 (9H, m), 2.70–3.13 (6H, m), 4.19–4.22 (1H, m), 6.58–7.52 (3H, m).

Step e: (4-Amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone

This compound was prepared by the method of Example 2 Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.151 g).

¹H NMR: δ(CDCl₃) 1.95–2.43 (5H, m), 2.69–2.81 (3H, m), 3.42–3.91 (10H, m), 4.19–4.23 (1H, m), 6.56–7.25 (6H, m).

Melting point: 138–139° C.

EXAMPLE 5

This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (Compound 1 in Table II).

Step a: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

This compound was prepared by the method of Example 2, Step a using 4-(3,4-difluorophenoxy)piperidine to give the sub-title compound as a solid (0.48 g).

MS: APCI(+ve): 397 (M+H)

Step b: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl

This compound was prepared by the method of Example 2, Step b to give the sub-title compound as a solid (0.36 g).

MS: APCI(+ve): 297 (M+H)

Step c: (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone

This compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.133 g).

¹H NMR: δ(CDCl₃) 1.50–1.60 (2H, m), 1.85–1.93 (4H, m), 2.04–2.08 (2H, m), 2.58–2.62 (2H, m), 2.69–2.75 (1H, m), 2.86–2.90 (4H, m), 3.86 (3H, s), 3.86 (2H, m), 4.25–4.30 (1H, m), 6.50–6.61 (1H, m), 6.65 (1H, dd), 6.70–6.75 (1H, m), 6.85 (1H, dt), 6.94 (1H, s), 7.01–7.09 (1H, m).

EXAMPLE 6

This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone (Compound 2 in Table II).

Step a: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

This compound was prepared by the method of Example 2, Step a using 3-oxo-piperidine-1-carboxylic acid tert-butyl ester to give the sub-title compound as a solid (0.946 g).

MS: APCI(+ve): 397 (M+H)

Step b: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl

This compound was prepared by the method of Example 2, Step b to give the sub-title compound as a solid (0.706 ).

MS: ESI(+ve): 297 (M+H)

Step c: (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone

This compound was prepared by the same method as Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.070 g).

¹H NMR: δ(CDCl₃) 1.41–1.67 (4H, m), 1.73–1.80 (2H, m), 1.86–2.00 (2H, m), 2.44 (3H, m), 3.00–3.13 (2H, m), 2.79–2.91 (2H, m), 3.82 (3H, s), 3.97–4.01 (1H, d), 4.14–4.17 (1H, d), 4.32 (1H, sept), 4.89 (2H, s), 6.67 (1H, d), 6.75–6.79 (1H, m), 6.80 (1H, dd), 6.87 (1H, s), 6.98–7.06 (1H, m), 7.27 (1H, q).

EXAMPLE 7

This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl (Compound 280 in Table I).

The product of Example 2, Step b (0.2 g) was dissolved in acetone (4 ml). Potassium carbonate [0.134 g dissolved in H₂O (1.2 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.168 g) and the reaction left to stir for 1 hr. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried with Na₂SO₄ and concentrated. Purification reverse phase HPLC (with a gradient eluent system (25% MeCN/NH₄OAc_(aq) (0.1%) to 95% MeCN//NH₄OAc_(aq) (0.1%)) gave the title compound as a solid (0.077 g).

¹H NMR: δ(DMSO-D6) 1.45–1.58 (4H, m), 1.79–1.90 (4H, m), 2.28–2.46 (5H, m), 2.66–2.73 (2H, m), 3.67–3.71 (2H, m), 4.35–4.43 (1H, m), 6.93–8.60 (9H, m).

Melting point: 139–140° C.

EXAMPLE 8

This Example illustrates the preparation of 4-(3,4-difluoro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl (Compound 3 in Table II).

This compound was prepared by the method of Example 7 using product of Example 5, step b to give the title compound as a solid (0.095 g).

¹H NMR: δ(CDCl₃) 1.67–1.80 (4H, m), 1.87–2.01 (1H, t), 2.30 (1H, t), 2.39–2.50 (2H, m), 2.74–2.78 (2H, m), 3.89 (2H, d), 4.16–4.20 (1H, m), 6.56–6.60 (1H, m), 6.67–6.63 (1H, m), 7.03 (1H, q), 7.26 (1H, t), 7.52 (1H, d), 7.53 (1H, d), 7.70 (1H, d), 7.76 (1H, dt), 8.60 (1H, d).

Melting point: 128–129° C.

EXAMPLE 9

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone (Compound 293 Table I).

Step 1: Preparation of 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

To 1-tert-butoxycarbonyl-4-piperidone (200 g, 1.01 mol) in tetrahydrofuran (THF) (1500 ml) was added 4-hydroxypiperidine (78.1 g, 0.77 mol). The resultant slurry was stirred for 30 minutes before cooling the reaction mixture with ice/water, acetic acid (47 ml) is then added (exotherm) which caused precipitation. The slurry was allowed to warm to room temperature before the addition of sodium triacetoxyborohydride (236 g, 1.12 mol) which was washed in with THF (500 ml). The resultant slurry was stirred overnight at room temperature. To the reaction mixture was added water (2000 ml) to give a solution. The solution was then extracted with diethyl ether (3×1800 ml). The aqueous phase was basified with 10% aq NaOH (950 ml) and extracted with dichloromethane (DCM) (3×1500 ml). The combined DCM layers are dried (MgSO₄), filtered and the solvent removed to give the sub-titled compound as a yellow viscous oil, (177 g, 81%; MS: (M+H) 285).

Step 2: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

To a solution of potassium tert-butoxide (139.0 g, 1.24 mol) in THF (500 ml) was added a solution of the product of Step 1 (176.2 g, 0.62 mol) in THF (1000 ml). The reaction mixture was stirred 10 minutes before the additon of 3,4 dichlorofluorobenzene (122.8 g, 0.74 mol), this caused a green colouration that subsequently faded. The reaction mixture was then heated at reflux for 90 minutes. The reaction mixture was then cooled to room temperature before the addition of saturated NaHCO₃ (1600 ml). The layers were separated and the organic layer stripped to leave an orange semi-solid. The solid was dissolved in DCM (1500 ml) and dried (MgSO₄), filtered and the solvent removed. To the resultant solid was added methyl tert-butyl ether (MTBE) (54 ml) and iso-hexane (1000 ml) to give a slurry which was stirred overnight. The slurry was then filtered and washed with isohexane (200 ml) and the solid dried in vacuo at 50° C. to give the sub-titled compound as a pale powder, (211.6 g, 80%; MS: (M+H) 429).

Step 3: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidine

The product of Step 2 (10.15 g, 23.6 mmol) was dissolved in dichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol) added and the resultant solution stirred. After 90 minutes the dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resultant oil was partitioned between ethyl acetate (100 ml) and 2M aq NaOH (100 ml). The layers were separated and the organics extracted with 10% aq citric acid (100 ml). The layers were separated and the aqueous basified with 2M aq NaOH and extracted with ethyl acetate (200 ml). The organics were dried (MgSO₄), filtered and the solvent removed to give the sub-titled product as a pale oil which solidified on standing (4.62 g, 59%; MS: (M+H) 329).

Step 4: Preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone

Oxalyl chloride (55 ml, 0.63 mol) was added dropwise over 10 minutes to a stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) in DCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for 2 hours at room temperature. The solution was then evaporated to give a solid that was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (275 ml) and was added over 10 minutes to a stirred solution of the product of Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) in dichloromethane (125 ml). The resultant solution was stirred at room temperature for 16 hours. The solution was then washed with water (500 ml), 1M aq NaOH (500 ml) and water (2×500 ml). The organic phase was dried (MgSO₄), filterered and the solvent removed to give a pale yellow foam. The foam was triturated with diethyl ether to give the title compound (12.96 g, 76%).

Melting point 141° C.

¹H NMR: (400 MHz, CDCl₃) δ 1.39–1.63 (1H, m), 1.72–2.04 (6H, m), 2.42–2.68 (2H, m), 2.73–2.92 (3H, m), 3.00–3.08 (1H, m), 3.23 (1H, s), 3.28 (2H, s), 3.34–3.40 (1H, m), 3.46–3.52 (1H, m), 4.21–4.30 (1H, m), 4.62–4.68 (1H, m), 4.80–4.86 (1H, m), 6.72–6.76 (1H, m), 6.97–7.00 (1H, m), 7.28–7.32 (1H, m), 7.32–7.37 (1H, m), 7.56–7.61 (1H, m), 7.64–7.70 (1H, m), 8.05–8.10 (1H, m).

EXAMPLE 10

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone (Compound 281 Table I).

Oxalyl chloride. (30 mls, 0.35 mol) was added dropwise over 10 minutes to a stirred suspension of 3-methanesulfonyl-benzoic acid (6 g, 0.03) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 4 hours at room temperature. The solution was then evaporated under high vacuum to give a solid which was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (10 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (9.3 g, 0.028 mol) and triethylamine (8.4 ml, 0.06 mol) in dichloromethane (100 ml). The resultant solution was stirred at room temperature for 3 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) and water (2×100 ml). The organic phase was dried (MgSO₄), filterered and the solvent removed to give a pale yellow foam. The foam was dissolved in methanol (100 ml) and allowed to crystallise. The crystals were filtered, washed with methanol and then dried to give the title compound (12.2 g, 84%).

Melting point 157° C.

¹H NMR: (400 MHz, CDCl₃) δ 1.40–1.65 (2H, m), 1.75–1.85 (3H, m), 1.93–2.03 (3H, m), 2.42–2.51 (2H, m), 2.58 (1H, tt), 2.74–2.91 (3H, m), 3.00–3.14 (1H, m), 3.07 (3H, s), 3.62–3.76 (1H, m), 4.27 (1H, septet), 4.69–4.80 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.31 (1H, d), 7.64 (1H, t), 7.69 (1H, dt), 7.97–7.98 (1H, m), 8.00 (1H, dt).

The hydrochloride salt (melting point 159° C.) was prepared by evaporation to dryness of a clear solution of Compound 281 of Table I and HCl in ethanol.

EXAMPLE 11

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-thiophen-5-yl)-methanone (Compound 332 of Table I).

Oxalyl chloride (32 ml, 0.37 mol) was added dropwise over 10 minutes to a stirred suspension of 5-(methylsulfonyl)-2-thiophenecarboxylic acid (6.64 g, 0.032 ) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 2 hours at room temperature. The solution was then removed to give a solid which was redissolved in dichloromethane and the solvent again removed to give a yellow solid. The solid acid chloride was dissolved in DCM (150 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (10 g, 0.03 mol) and triethylamine (9 ml, 0.065 mol) in dichloromethane (300 ml). The resultant solution was stirred at room temperature for 2 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) and water (300 ml). The organic phase was dried (MgSO₄), filterered and the solvent removed to give an orange foam. The solid was dissolved in dichloromethane (200 ml) and purified by chromatography using ethyl acetate and then acetone as the eluant. The purified material was precipitated from acetone by the addition of iso-hexane. The crystals were filtered, washed with isohexane and then dried to give the title compound (11.5 g, 74%).

Melting point: 153–154° C.

¹H NMR (399.98 MHz, DMSO-D6) δ 1.42–1.48 (2H, m), 1.56–1.62 (2H, m), 1.77–1.84 (2H, m), 1.90–1.96 (2H, m), 2.37–2.43 (2H, m), 2.56–2.63 (2H, m), 2.75–2.80 (2H, m), 2.89–3.14 (2H, m), 3.29–3.32 (1H, m), 3.41 (3H, s), 4.41–4.45 (1H, m), 6.98 (1H, dd), 7.25 (1H, d), 7.49 (2H, q), 7.77 (1H, d).

EXAMPLE 12

This Example illustrates the preparation of [4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone (Compound 1 of Table IV)

A solution of 4-(2-methyl-4-chloro-phenoxy)-piperidine (0.87 mmol) and 1-(3-methanesulfonyl-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml) and glacial acetic acid (1 mmol) was stirred at room temperature for 1 hour after which sodium triacetoxy borohydride (2 mmol) was added. The resulting mixture was stirred at RT for 24 hours, evaporated on to silica (2 g) and placed on to a Mega Bond elut cartridge (10 g Silica). The product was eluted with DCM/MeOH mixtures and further purified by Reverse Phase preparative chromatography, MeOH/aqueous TFA gradient on a Symmetry column. The free base was isolated by dissolving in EtOAc and washing with sodium bicarbonate solution, drying the organic layer with MgSO₄ and evaporation left the product as a white solid (0.047 g; M.pt. 83–84° C.).

¹H NMR (300 MHz, DMSO-D6) δ 1.2–2.8 (bm, 14H), 2.15 (s, 3H), 3.1 (bm, 1H), 3.25 (s, 3H), 3.5 (bm, 1H), 4.4 (bm, 1H), 4.5(bm, 1H), 7.0 (d, 1H), 7.12 (m, 1H), 7.2 (d, 1H), 7.7 (m, 2H), 7.9 (s, 1H), 8.0 (dd, 1H).

EXAMPLE 13

This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone ditrifluoroacetate (Compound 23 of Table IV).

A solution of the 4-(4-chloro-2-methyl-phenoxy)-piperidine (0.87 mmol) and 1-(4-nitro-3-methoxy-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml) and glacial acetic acid (1 mmol) was stirred at RT for 1 hour after which sodium triacetoxy borohydride (2 mmol) was added. The resulting mixture was stirred at RT for 24 hours, evaporated on to silica (2 g) and placed on to a Mega Bond elut cartridge (10 g Si). The product was eluted with DCM/MeOH mixtures and further purified by SCX, eluting the product with 10% aq NH₃ in MeOH. The nitro compound was dissolved in THF (10 ml) and hydrogenated over 10% Pd on C at 3 atmospheres in Peteric apparatus. The mixture was filtered and the filtrate evaporated, the residue was then purified by RPHPLC, using a Symmetry column and eluting with MeOH/aqueous TFA mixtures. The product was isolated as the trifluoroacetate by evaporation of the appropriate HPLC fractions (0.046 g; m.pt. 84–85° C.).

¹H NMR (400 MHz, DMSO-D6) δ 1.4–2.4 (m, 13H), 2.9 (m, 2H), 3.15 (m, 2H), 3.4 (m, 1H), 3.55 (m, 2H), 3.8 (s, 3H), 4.2 (bs, 2H), 4.55 and 4.8 (2bm, 1H), 6.68 (d, 1H), 6.82 (d, 1H), 6.85 (s, 1H), 7.0–7.22 (m, 2H), 7.25 (s, 1H), 9.5 (bm, 1H).

EXAMPLE 14

This Example illustrates the preparation of 2-[1′-(3-methanesulfonyl-benzoyl)-[1,4′]bipiperidinyl-4-yloxy]-5-trifluoromethyl-benzonitrile trifluoroacetate (Compound 291 of Table IV).

The product of Method E (183 mg, 0.5 mmol) was dissolved in DMSO (2 ml) and treated with sodium hydride (22 mg 1 equiv. of 60%) under an inert atmosphere. After stirring the mixture at RT for 1 hour, 2-fluoro-5-trifluoromethyl-benzonitrile (1 equiv.) was added. After stirring at RT for 24 hours, the reaction mixture was acidified (glacial acetic acid) and filtered. The filtrate was purified by RPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as the trifluoroacetate salt (0.06 g; m.pt. 110–111° C.).

¹H NMR (400 MHz, DMSO-D6) δ 1.0–3.8 (m, 20H), 4.5–5.3 (m, 2H), 7.5 (d, 1H), 7.75 (m, 3H), 8.02 (m, 2H).

EXAMPLE 15

This Example illustrates the preparation of (3-methanesulfonyl-phenyl)-[4-(6-methyl-pyridin-2-yloxy)-[1,4′]bipiperidinyl-1′-yl]-methanone trifluoroacetate (Compound 292 of Table IV).

The product of Method E (1 mmol) and potassium tert-butoxide (2 mmol) were stirred together in dry THF (20 ml) at RT. After 10 mins 2-fluoro-6-methyl-pyridine (1 mmol) was added and the reaction mixture stirred at reflux overnight. The reaction mixture was cooled, diluted with water and extracted into ethyl acetate (3×50 ml). The combined extracts were dried (MgSO₄) and evaporated. The residue was purified by RPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as the trifluoroacetate salt (0.03 g; m.pt. 61–62° C.).

¹H NMR (400 MHz, DMSO-D6) δ 1.6–3.8 (m, 15H), 2.4 (s, 3H), 3.3 (s, 3H), 4.5–5.4 (m, 3H), 6.6 (m, 1H), 6.02 (dd, 1H), 7.6 (q, 1H), 7.82 (m, 2H), 7.95 (s, 1H), 8.02 (m, 1H), 9.7 (bs, 1H)

EXAMPLE 16

This Example illustrates the preparation of N-{3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide (Compound 583 of Table I).

To (3-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.133 g) in pyridine (2 mL) was added methanesulfonyl chloride (0.024 ml) and the reaction left to stir for 5 minutes. The solvent was evaporated, water (0.5 mL) added and the solvent re-evaporated. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) gave the title compound (0.050 g; m.pt. 94–95° C.).

¹H NMR (399.978 MHz, CDCl₃) δ 1.59–2.09 (8H, m), 2.22 (2H, br s), 2.54–2.60 (1H, m), 2.81 (2H, br s), 3.02 (5H, br s), 3.51–3.75 (1H, br m), 4.25–4.28(1H, m), 4.29 (1H, br s), 6.70–7.52 (8H, m).

EXAMPLE 17

This Example illustrates the preparation of N-{2-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide (Compound 587 of Table I).

To a solution of (2-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.2 g) in pyridine (2 ml) at 0° C. was added methane sulphonyl chloride (0.039 ml). The mixture was allowed to warm to room temperature and the pyridine removed by evaporation. The residue was azeotroped with water and the product purified by RPHPLC (Symmetry column, eluting 25% to 95% MeCN/0.1% NH₄OAc aq at 20 ml/min over 6 minutes) to give the product as a colourless solid (0.09 g).

¹H NMR: (399.978 MHz, CDCl₃) δ 1.49–1.69 (5H, m), 1.77–1.84 (2H, m), 1.87–1.94 (1H, m), 1.95–2.02 (2H, m), 2.43–2.50 (2H, m), 2.59 (1H, tt), 2.78–2.84 (2H, m), 2.87–3.03 (1H, m), 3.08 (3H, s), 3.17 (1H, sextet), 4.27 (1H, septet), 6.75 (1H, dd), 6.99 (1H, d), 7.15 (1H, td), 7.24 (1H, d), 7.31 (1H, d), 7.43 (1H, td), 7.62 (1H, d).

EXAMPLE 18

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(1-methanesulfonyl-1H-indol-3-yl)-methanone hydrochloride (Compound 592 of Table I).

To a solution of Compound 471 of Table I (0.1 7 g) in dimethylformamide (3 ml) at 0° C. under an atmosphere of nitrogen, was added sodium hydride (0.014 g of a 60% suspension in oil). The mixture was stirred for 5 minutes then methanesulphonyl chloride (0.027 ml in 1 ml of dimethylformamide) was added and then mixture allowed to warm to room temperature over 12 hours. The reaction mixture was partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO₄) and the solvent removed by evaporation. The residue was purified by RPHPLC (Symmetry, 25% to 95% MeCN/0.1% NH₄OAc aq over 6 minutes, 20 ml/min, 220 nm) to give a colourless solid (0.062 g; m.pt. 173–175° C.).

¹H NMR: (299.944 MHz DMSO-D6) δ 1.72–1.87 (2H, m), 2.01–2.34 (5H, m), 2.48–2.55 (1H, m), 2.98–3.13 (2H, m), 3.13–3.27 (2H, m), 3.39–3.47 (2H, m), 3.53–3.62 (2H, m), 3.64 (3H, s), 4.35–4.58 (1H, m), 4.65–4.76 (1H, m), 7.12 (1H, dd), 7.39–7.48 (2H, m), 7.52 (1H, t), 7.61 (1H, t), 7.79 (1H, d), 7.8.8 (1H, s), 7.95 (1H, d).

EXAMPLE 19

This Example illustrates the preparation of 1-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-2-phenyl-3-piperazin-1-yl-propan-1-one (Compound 595 of Table I).

Compound 575 of Table I (0.178 g) was treated with 6N hydrochloric acid (5 ml) and stirred at room temperature for 24 hours. 2N Sodium hydroxide solution was added and the reaction mixture extracted with ethyl acetate. The organic extracts were combined, washed with water, dried (MgSO₄) and evaporated to give a white solid. Purification was by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)). (Any excess NH₄OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO₃ followed by drying of the organics with MgSO₄ and evaporation of solvent.) The title compound was a white solid (0.087 g).

¹H NMR (399.98 MHz, DMSO-D6) δ 1.20–1.95 (9H, m), 2.10–2.53 (9H, m), 2.59–2.65 (2H, m), 2.70–2.77 (1H, m), 2.89–3.12 (4H, m), 4.02–4.47 (4H, m), 6.89–7.00 (1H, m), 7.16–7.32 (6H, m), 7.44–7.52 (1H, m).

EXAMPLE 20

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-1-oxy-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone.

The product Example 10 (0.100 g) in dichloromethane (5 ml) was treated with m-chloroperbenzoic acid (0.043 g) and the reaction stirred at room temperature for 0.5 hours. Saturated aqueous sodium hydrogencarbonate was added and the reaction mixture extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO₄) and evaporated to give a brown foam. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) gave the title compound as a white solid (0.021 g).

¹H NMR (299.946 MHz, DMSO-D6) δ 1.70–2.91 (15H, m), 3.24–3.44 (3H, m), 3.55–3.68 (1H, m), 4.55–4.76 (2H, m), 6.99–7.06 (1H, m), 7.29–7.33 (1H, m), 7.53 (1H, dd), 7.71–7.79 (2H, m), 7.93 (1H, s), 7.99–8.05 (1H, m).

EXAMPLE 21

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 1 of Table I).

To a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.1 g, see step b of Example 2) in dichloromethane (5 ml) and triethylamine (0.2 ml) was added benzoyl chloride (0.045 ml) and the reaction mixture was stirred for 2 hours. The mixture was washed with water, dried (MgSO₄), filtered and the solvents evaporated to leave a gum. Purification by RPHPLC [with an eluent system (50% MeCN/0.1% NH₄OAc aq), any excess NH₄OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO₃ followed by drying of the organics with MgSO₄ and evaporation of solvent] and trituration of the resulting product with diethyl ether gave a solid which was filtered and dried to give the title compound (0.120 g; m.pt. 122° C.).

¹H NMR (299.944 MHz CDCl₃) δ 1.42–1.62 (2H, m), 1.78–1.82 (3H, m), 1.95–2.01 (3H, m), 2.39–2.69 (3H, m), 2.69–3.09 (4H, m), 3.63–3.95 (1H, m), 4.24–4.29 (1H, m), 4.62–4.89 (1H, m), 6.73–6.77 (1H, m), 6.99 (1H, d), 7.26–7.29 (1H, m), 7.39 (5H, s).

EXAMPLE 22

This Example illustrates the preparation of [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone (Compound 4 of Table V).

Step 1: 4-(3,4-dichloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester

4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.18 g) and 3,4-dichlorothiophenol (6.15 ml) were stirred together in acetonitrile (200 ml) and potassium carbonate (8.86 g) was added. The mixture was heated at reflux for 18 hours after which water was added and the resulting mixture extracted with dichloromethane. The organic extracts were combined, washed with water, dried (MgSO₄) and evaporated to give the sub-title compound (14.58 g).

¹H NMR (299.944 MHz, CDCl₃) δ 1.45 (9H, s), 1.49–1.62 (2H, m), 1.87–1.96 (2H, m), 2.89–2.98 (2H, m), 3.16–3.26 (1H, m), 3.91–4.01 (2H, m), 7.21–7.57 (3H, m).

Step 2: 4-(3,4-dichloro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester

The product from Step 1(1 g) and m-chloroperbenzoic acid (1.19 g) were stirred at ambient temperature in dichloromethane (10 ml) for 18 hours. Sodium metabisulphite (1.19 g) in water (5 ml) was added and stirring was continued for 0.5 hours after which the reaction mixture was extracted with dichloromethane. The combined organics were washed with saturated sodium bicarbonate solution, dried (MgSO₄) and evaporated to give the sub-title compound (0.34 g).

¹H NMR (399.978 MHz, CDCl₃) δ 1.45 (9H, s), 1.56–1.65 (2H, m), 1.94–2.00 (2H, m), 2.62–2.70 (2H, m), 3.01–3.09 (1H, m), 4.21–4.30 (2H, m), 7.66–7.70 (2H, m), 7.93–7.98 (1H, m).

Step 3: 4-(3,4-dichloro-benzenesulfonyl)-piperidine

The product of step 2 was deprotected following the procedure of Example 1 step b. ¹H NMR (299.944 MHz, CDCl₃) δ 1.64–1.71 (2H, m), 1.96–2.05 (2H, m), 2.55–2.64 (2H, m), 2.99–3.10 (1H, m), 3.19–3.27 (2H, m), 7.66–7.71 (2H, m), 7.92–7.98 (1H, m).

Step 4: 4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

The product of step 3 was used in a reductive amination with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure of Example 2 step a.

Step 5: 4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl

The product of step 4 was deprotected following the procedure of Example 2 step b. ¹H NMR (299.946 MHz, DMSO-D6) δ 1.22–1.61 (7H, m), 1.77–1.83 (2H, m), 2.09–2.16 (1H, m), 2.25–2.45 (3H, m), 2.87–2.98 (4H, m), 3.35–3.43 (1H, m), 7.81 (1H, dd), 7.96 (1H, d), 8.05 (1H, d)

Step 6: [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone

The product of step 5 was coupled to 4-methanesulfonyl-benzoic acid following the procedure of Example 2 step c.

1H NMR (299.946 MHz, DMSO-D6) δ 1.34–1.62 (5H, m), 1.70–1.85 (4H, m), 2.13 (3H, t), 2.72–3.04 (4H, m), 3.27 (3H, s), 3.37–3.48 (1H, m), 4.44–4.52 (1H, m), 7.63 (2H, d), 7.81 (1H, dd), 7.95–8.00 (3H, m), 8.06 (1H, d). [4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 5 of Table V). The product of step 5 was coupled to benzoic acid following the procedure of Example 2 step c. ¹H NMR (299.946 MHz, DMSO-D6) δ 1.31–1.69 (5H, m), 1.82 (3H, d), 2.15 (2H, d), 2.69–2.75 (1H, m), 2.90–2.97 (4H, m), 3.33–3.43 (1H, m), 3.48–3.63 (1H, m), 4.42–4.53 (1H, m), 7.39 (5H, dt), 7.81 (1H, dd), 7.96 (1H, d), 8.06 (1H, d).

EXAMPLE 23

This Example illustrates the preparation of 3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-1-ethyl-7-methyl-1H-[1,8]naphthyridin-4-one (Compound 534 of Table I).

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (0.155 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO₃ solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO₄ and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) %)) (any excess NH₄OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO₃ followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.184 g; m.pt. 189–190° C.)

MS: APCI⁺(M+H) 543

¹H NMR (299.946 MHz, DMSO-D6) δ 1.37 (3H, t), 1.47–1.69 (5H, m), 1.78–1.84 (1H, m), 1.89–1.97 (2H, m), 2.36–2.41 (2H, m), 2.49–2.56 (1H, m), 2.66 (3H, s), 2.70–2.79 (3H, m), 2.95–3.04 (1H, m), 3.52–3.59 (1H, m), 4.38–4.57 (4H, m), 6.95–6.99 (1H, m), 7.22–7.24 (1H, m), 7.35–7.40 (1H, m), 7.46–7.51 (1H, m), 8.37 (1H, s), 8.43–8.45 (1H, m).

EXAMPLE 24

This Example illustrates the preparation of 4-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-2H-isoquinolin-1-one (Compound 572 of Table I).

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO₃ solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO₄ and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%))) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO₃ followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.153 g).

MS: APCI⁺(M+H) 500

¹H NMR (299.944 MHz CDCl₃) δ 1.37–1.66 (2H, m), 1.73–1.88 (3H, m), 1.93–2.05 (3H, m), 2.41–2.51 (2H, m), 2.52–2.63 (1H, m), 2.75–2.86 (2H, m), 2.86–3.09 (2H, m), 3.71–3.90 (1H, m), 4.23–4.32 (1H, m), 4.77–4.93 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.27–7.32 (3H, m), 7.54–7.67 (1H, m), 7.57 (1H, t), 7.74 (1H, t), 8.46 (1H, d).

EXAMPLE 25

This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone (Compound 579 of Table I).

Step a: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

To a solution of 2-amino-5-fluoropyridine (1.12 g) in diethyl ether (25 ml) was added ethyl bromopyruvate (1.25 ml). the mixture was stirred for 1 hour. The resultant solid was filtered off, suspended in ethanol and heated at reflux for 4 hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate solution (100 ml). The organic layer was separated, dried, (magnesium sulfate) and the solvent removed by evaporation. The residue was purified by flash chromatography (silica) eluting with ethyl acetate:hexane (3:1) to give the sub-title compound as a colourless solid (1.12 g).

MS: ES⁺(M+H) 209

¹H NMR (399.98 MHz, CDCl₃) δ 1.44 (3H, t), 4.46 (2H, q), 7.19 (1H, ddd), 7.68 (1H, dd), 8.07–8.09 (1H, m), 8.19 (1H, s).

Step b: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid

A solution of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1 g) in 4N HCl was refluxed for 4 hours. The solvent was evaporated to give the sub-title compound as a white solid (0.86 g).

MS: ES⁺(M+H) 181

¹H NMR (399.98 MHz, DMSO-D6) δ 7.81–7.89 (2H, m), 8.71 (1H, s), 9.03 (1H, s).

Step c: [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO₃ solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO₄ and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) (any excess NH₄OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO₃ followed by drying of the organics with magnesium sulfate and evaporation of solvent) gave the title compound (0.104 g).

MS: APCI⁺(M+H) 491

¹H NMR (399.978 MHz, CDCl₃) δ 1.61 (1H, qd), 1.75–2.02 (7H, m), 2.42–2.51 (2H, m), 2.59–2.67 (1H, m), 2.75–2.86 (3H, m), 3.12–3.21 (1H, m), 4.23–4.29 (1H, m), 4.76–4.85 (1H, m), 5.23–5.32 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.16 (1H, ddd), 7.30 (1H, d), 7.58 (1H, dd), 8.07 (2H, s).

EXAMPLE 26

This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid phenylamide (Compound 309 of Table IV).

Phenylisocyanate(0.078 ml) was added to a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see Example 2 step b) in dichloromethane (5 ml). The mixture was stirred at 23° C. for 16 hours. The resulting precipitate was filtered, washed with dichloromethane (2×5 ml) then crystallised from acetonitrile to afford the title compound as a solid (0.2 g; melting point 215–216° C.).

¹H NMR (DMSO-D6) δ 1.35 (2H, qd), 1.53–1.62 (2H, m), 1.72–1.78 (2H, m), 1.89–1.96 (2H, m), 2.36–2.42 (2H, m), 2.44–2.52 (1H, m), 2.72–2.78 (4H, m), 4.15 (2H, d), 4.39–4.45 (1H, m), 6.91 (1H, tt), 6.98 (1H, dd), 7.19–7.23 (2H, m), 7.25 (1H, d), 7.43–7.46 (2H, m), 7.49 (1H, d), 8.46 (1H, s).

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbothioic acid phenylamide was prepared using the methodology of Example 26 and employing phenylisothiocyanate, (melting point 162–163° C.). ¹H NMR: (DMSO-d6) δ 1.39–1.49 (2H, m), 1.53–1.62 (2H, m), 1.79 (2H, d), 1.89–1.96 (2H, m), 2.39 (2H, t), 2.54–2.63 (1H, m), 2.73–2.80 (2H, m), 3.04 (2H, t), 4.39–4.46 (1H, m), 4.72 (2H, d), 6.98 (1H, dd), 7.06–7.10 (1H, m), 7.23–7.30 (5H, m), 7.49 (1H, d), 9.24 (1H, s).

EXAMPLE 27

This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid (3-methanesulfonyl-phenyl)-amide (Compound 54 of Table IV).

Hydrogen peroxide (100 μl, 30%) was added to a cooled (0° C.) solution of Compound 312 of Table IV (0.13 g) in trifluoroacetic acid (1 ml). The mixture was allowed to reach ambient temperature and stirred for a further 1 hour. The solution was quenched with water (5 ml), basified to pH11 with 2M sodium hydroxide solution and extracted with ethyl acetate. The organic solution was separated, washed with water(2×5 ml), dried (MgSO₄), filtered and the filtrate evaporated to leave a gum. The gum was dissolved in acetonitrile and purified by RPHPLC (Nova Pak column) eluting with acetonitrile/0.1% ammonium acetate aq (1:1). The required fractions were evaporated and then lyophilised to give the title compund as a colourless powder (0.03 g).

¹H NMR (DMSO-D6) δ 1.31–1.42 (2H, m), 1.53–1.62 (2H, m), 1.77 (2H, d), 1.89–1.96 (2H, m), 2.36–2.43 (3H, m), 2.74–2.82 (4H, m), 3.16 (3H, s), 4.18 (2H, d), 4.42 (1H, septet), 6.98 (1H, dd), 7.25 (1H, d), 7.44–7.52 (3H, m), 7.80–7.83 (1H, m), 8.09 (1H, t), 8.90 (1H, s).

Selected proton NMR data and/or melting point data are provided for certain further compounds in Tables VI and VII below.

TABLE VI Compound (Table no.) NMR data  3(I) δ (D₂O) 1.97–1.69(2H, m), 2.21–2.08(2H, m), 2.51–2.23(4H, m), 3.07–2.96(1H, m), 3.31–3.17(2H, m), 3.45–3.32(2H, m), 3.56–3.45(1H, m), 3.75–3.56(2H, m), 4.88–4.70(3H, m), 7.07–7.02(1H, m), 7.36–7.30(1H, m), 7.46–7.37(1H, m), 7.55(2H, d), 7.74–7.72(1H, m)  8(I) δ (CDCl₃) 1.67–1.41(2H, m), 1.86–1.76(3H, m), 2.04–1.93(3H, m), 2.51–2.42(3H, m), 2.62–2.56(1H, m), 2.88–2.76(3H, m), 3.06(1H, t), 3.66(1H, d), 4.28(1H, septet), 4.76(1H, d), 6.75(1H, dd), 6.99(1H, d), 7.31(1H, d), 7.56(2H, d), 8.28(2H, d)  18(I) δ (CD₃OD) 1.59–1.41(2H, m), 1.83–1.68(2H, m), 2.08–1.93(4H, m), 2.56–2.48(4H, m), 2.68–2.61(1H, m), 2.91–2.80(3H, m), 3.15–3.02(1H, m), 3.71–3.57(1H, m), 4.23–4.14(1H, m), 4.40(1H, septet), 4.50(3H, s), 4.75–4.57(1H, m), 6.91(1H, dd), 7.12(1H, d), 7.40(1H, d), 7.66(2H, d), 8.04(2H, d)  36(I) δ (CD₃OD) 1.62–1.42(2H, m), 1.94–1.72(3H, m), 2.11–1.98(3H, m), 2.61–2.52(2H, m), 2.95–2.82(3H, m), 3.15(1H, t), 3.68–3.63(1H, m), 4.42(1H, septet), 4.71–4.67(2H, m), 6.91(1H, dd), 7.11(1H, d), 7.40(1H, d), 7.60(2H, d), 7.86(2H, d)  37(I) δ (CD₃OD) 2.06–1.76(3H, m), 2.45–2.12(5H, m), 3.05–2.88(1H, m), 3.42–3.25(3H, m), 3.71–3.50(2H, m), 3.93–3.74(1H, m), 4.63(1H, septet), 4.94–4.82(2H, m), 7.03–6.95(1H, m), 7.24(1H, dd), 7.47–7.42(1H, m), 7.71–7.66(1H, m), 7.78(1H, td), 7.90–7.86(2H, m) 149(I) δ (CDCl₃) 1.50–1.27(2H, m), 1.90–1.75(5H, m), 2.02–1.92(2H, m), 2.56–2.39(4H, m), 2.63(1H, t), 2.81–2.72(2H, m), 3.09–3.01(3H, m), 3.82(2H, s), 3.91(1H, d), 4.25(1H, septet), 4.67(1H, d), 6.75(1H, dd), 6.99(1H, d), 7.31(1H, dd), 7.45(2H, d), 7.90(2H, d) 203(I) δ (DMSO-D6) 1.61–1.44(2H, m), 2.24–2.01(4H, m), 2.61–2.53(2H, m), 3.16–2.99(2H, m), 3.60–3.30(5H, m), 3.67(2H, s), 3.77(3H, s), 4.13(1H, d), 4.53(1H, d), 4.69–4.60(1H, m), 7.05(1H, ddd), 7.14(1H, d), 7.42–7.25(3H, m), 7.55(2H, dd), 10.98–10.78(3H, m) 205(I) δ ((CD₃)₂CO) 1.26(2H, quintet), 1.76–1.58(4H, m), 1.98–1.90(2H, m), 2.42–2.35(2H, m), 2.58–2.45(2H, m), 2.81–2.71(2H, m), 3.00(1H, t), 3.70(2H, s), 4.00(1H, d), 4.39(2H, septet), 4.51(1H, d), 6.92(1H, dd), 7.07–7.01(2H, m), 7.13(1H, d), 7.30–7.25(2H, m), 7.40(1H, d) 220(I) δ (DMSO-D6) 1.58–1.44(2H, m), 2.28–1.97(5H, m), 2.59–2.53(2H, m), 3.18–2.93(3H, m), 3.34–3.25(1H, m), 3.51–3.36(2H, m), 3.66–3.56(2H, m), 4.11(1H, d), 4.53(1H, d), 4.64(1H, septet), 6.92–6.82(2H, m), 6.99(1H, d), 7.10–7.03(1H, m), 7.36(1H, dd), 7.55(1H, ddd), 10.99–10.87(1H, m) 225(I) δ ((CD₃)₂CO) 1.71–1.51(2H, m), 2.13–2.08(2H, m), 2.40–2.21(3H, m), 2.61–2.54(1H, m), 3.05(1H, t), 3.55–3.15(6H, m), 3.69–3.61(2H, m), 4.16(1H, d), 4.76–4.63(2H, m), 4.91–4.86(1H, m), 6.78–6.76(2H, m), 7.12–7.02(3H, m), 7.32(1H, dd), 7.51(1H, dd) 244(I) δ (DMSO-D6) 1.55–1.42(2H, m), 2.25–1.96(6H, m), 2.66–2.54(2H, m), 3.14–2.96(2H, m), 3.32–3.26(1H, m), 3.51–3.35(2H, m), 3.62(3H, s), 3.71–3.64(2H, m), 3.74(6H, s), 4.14(1H, d), 4.54(1H, d), 4.66–4.58(1H, m), 6.53(2H, s), 7.04(1H, dd), 7.35(1H, d), 7.54(1H, tt) 253(I) δ (CDCl₃) 1.47–1.19(2H, m), 2.00–1.76(6H, m), 2.62–2.37(4H, m), 2.80–2.70(2H, m), 2.98(1H, t), 3.65(2H, s), 3.88(3H, s), 3.92–3.89(1H, m), 4.25(1H, septet), 4.68(1H, d), 6.77–6.72(1H, m), 6.89(1H, d), 6.94–6.92(2H, m), 7.01–6.96(2H, m), 7.30(1H, dd) 258(I) δ (DMSO-D6) 1.40–1.26(3H, m), 1.78–1.59(5H, m), 1.98–1.92(1H, m), 2.17(3H, s), 2.21(3H, s), 2.45–2.37(2H, m), 2.60–2.48(3H, m), 3.01(1H, t), 3.70–3.57(2H, m), 3.89(1H, d), 4.39(1H, septet), 4.55(1H, d), 7.00(1H, d), 7.13(1H, d), 7.41(1H, d), 7.95–7.89(3H, m) 267(I) δ (CDCl₃) 1.74–1.61(2H, m), 2.21–2.09(3H, m), 2.32–2.25(1H, m), 2.48(1H, t), 2.67–2.53(2H, m), 2.89(1H, t), 3.31–3.05(5H, m), 3.71(4H, s), 3.82(2H, s), 4.08(1H, d), 4.59–4.53(1H, m), 4.94(1H, d), 6.89(1H, dd), 6.93(1H, dd), 6.97(1H, d), 7.34(1H, d), 7.40(1H, d), 7.58–7.54(1H, m), 268(I) δ (CDCl₃) 1.24(1H, dq), 1.41(1H, dq), 1.88–1.72(4H, m), 2.00–1.91(2H, m), 2.53–2.37(3H, m), 2.59(1H, dt), 2.78–2.70(2H, m), 2.98(1H, t), 3.73(2H, s), 3.89(1H, d), 4.24(1H, septet), 4.68(1H, d), 6.74(1H, dd), 7.03–6.91(4H, m), 7.29–7.25(1H, m), 7.30(1H, d) 272(I) δ (CDCl₃) 1.18(1H, dq), 1.40(1H, dq), 1.86–1.68(4H, m), 2.00–1.91(2H, m), 2.43–2.35(2H, m), 2.48(1H, td), 2.57(1H, dt), 2.77–2.68(2H, m), 2.95(1H, dt), 3.74(2H, s), 3.91(1H, d), 4.23(1H, septet), 4.69(1H, d), 6.74(1H, dd), 6.98(1H, d), 7.35–7.23(6H, m) 274(I) δ (DMSO-D6) 1.74–1.59(5H, m), 1.77(3H, dq), 2.65–2.36(4H, m), 2.86–2.74(6H, m), 2.95(1H, t), 3.74(3H, s), 3.93(1H, d), 4.40(1H, septet), 4.53(1H, d), 6.73–6.70(1H, m), 6.80–6.78(2H, m), 6.93(1H, dd), 7.18–7.13(2H, m), 7.41(1H, d) 276(I) δ ((CD₃)₂CO) 1.63–1.51(2H, m), 2.02–1.98(2H, m), 2.21–2.15(2H, m), 2.58–2.31(4H, m), 2.96(1H, t), 3.40–3.03(4H, m), 3.60–3.49(2H, m), 3.72(3H, s), 4.02(1H, d), 4.63–4.55(1H, m), 4.77–4.72(1H, m), 6.76(1H, t), 6.84(1H, d), 6.96–6.93(1H, m), 7.03(1H, d), 7.11–7.07(1H, m), 7.16–7.15(1H, m), 7.37–7.31(1H, m) 286(I) δ (CD₃OD) 1.90–1.63(2H, m), 2.49–2.05(6H, m), 3.28–2.87(7H, m), 3.84–3.44(5H, m), 4.69–4.56(1H, m), 4.85–4.78(2H, m), 7.04–6.94(1H, m), 7.28–7.21(1H, m), 7.45(1H, t), 7.60–7.55(3H, m), 7.64–7.61(1H, m), 7.66(1H, t), 7.77–7.73(2H, m), 7.85–7.81(2H, m) 291(I) δ (CD₃OD) 1.98–1.71(3H, m), 2.46–2.11(5H, m), 3.18–2.98(1H, m), 3.45–3.26(2H, m), 3.70–3.46(4H, m), 3.86(3H, s), 4.66–4.56(1H, m), 4.84–4.80(2H, m), 7.04–6.94(3H, m), 7.27–7.20(1H, m), 7.47–7.42(3H, m) 293(I) δ (CD₃OD) 1.88–1.73(2H, m), 2.22–1.92(5H, m), 2.31(1H, d), 2.87–2.79(1H, m), 3.06–2.97(1H, m), 3.17(3H, s), 3.57–3.31(5H, m), 4.55–4.44(1H, m), 4.73–4.65(2H, m), 6.92–6.82(1H, m), 7.12(1H, td), 7.40–7.31(2H, m), 7.63(1H, dt), 7.75–7.68(1H, m), 7.99(1H, dt) 294(I) δ (CD₃OD) 1.98–1.70(2H, m), 2.45–2.08(6H, m), 2.97(1H, t), 3.21(3H, s), 3.41–3.21(3H, m), 3.72–3.49(3H, m), 4.67–4.56(1H, m), 4.95–4.81(2H, m), 7.03–6.94(1H, m), 7.27–7.20(1H, m), 7.47–7.42(1H, m), 7.74–7.62(1H, m), 8.02(1H, ddd), 8.13(1H, dd) 295(I) δ (CD₃OD) 2.04–1.74(3H, m), 2.36–2.12(4H, m), 2.48–2.40(1H, m), 3.03–2.87(1H, m), 3.43–3.15(3H, m), 3.80–3.47(3H, m), 4.68–4.58(1H, m), 4.85–4.80(2H, m), 5.13(2H, s), 7.03–6.96(1H, m), 7.27–7.21(1H, m), 7.46–7.42(1H, m), 7.63–7.56(3H, m), 7.79–7.69(4H, m), 8.12(1H, d) 296(I) δ (CD₃OD) 2.46–1.75(8H, m), 2.96(1H, t), 3.32(2H, s), 3.72–3.19(4H, m), 3.97–3.92(1H, m), 4.69–4.56(1H, m), 4.98–4.79(2H, m), 7.03–6.94(1H, m), 7.24(1H, d), 7.69–7.35(10H, m) 297(I) δ (CD₃OD) 1.66–1.51(2H, m), 1.89–1.69(3H, m), 2.08–1.96(3H, m), 2.71–2.50(3H, m), 3.01–2.81(3H, m), 3.24–3.10(1H, m), 3.84–3.71(1H, m), 4.46–4.38(1H, m), 4.79–4.67(1H, m), 6.92(1H, dd), 7.14(1H, d), 7.41(1H, d), 7.81(1H, dd), 8.39(1H, d), 8.71(1H, s) 298(I) δ (CD₃OD) 1.33(3H, t), 1.62–1.41(2H, m), 1.95–1.74(3H, m), 2.11–1.98(3H, m), 2.73–2.52(3H, m), 2.95–2.79(3H, m), 3.03(2H, q), 3.26–3.09(1H, m), 3.93–3.78(1H, m), 4.48–4.39(1H, m), 4.78–4.56(1H, m), 6.91(1H, dd), 7.11(1H, d), 7.42–7.34(5H, m) 299(I) δ (CD₃OD) 1.99–1.72(3H, m), 2.36–2.11(4H, m), 2.44(1H, d), 3.06–2.87(1H, m), 3.42–3.23(2H, m), 3.71–3.46(4H, m), 3.95–3.77(1H, m), 4.67–4.55(1H, m), 4.84–4.80(1H, m), 7.03–6.94(1H, m), 7.27–7.20(1H, m), 7.47–7.43(1H, m), 7.66–7.61(2H, m), 7.87–7.81(2H, m) 300(I) δ (CD₃OD) 1.96–1.72(3H, m), 2.33–2.09(4H, m), 2.46–2.41(1H, m), 3.02–2.87(1H, m), 3.43–3.22(3H, m), 3.72–3.47(3H, m), 3.93–3.78(1H, m), 4.66–4.56(1H, m), 4.84–4.80(1H, m), 7.03–6.94(1H, m), 7.28–7.21(1H, m), 7.47–7.43(1H, m), 7.59(2H, d), 7.83(2H, d) 301(I) (500.076MHz, DMSO-D6) δ 1.33–1.44(m, 2H), 1.55–1.60(m, 2H), 1.66–1.73(m, 1H), 1.78–1.86(m, 1H), 1.91(s, 3H), 1.91–1.96(m, 2H), 2.05(s, 3H), 2.39(t, 2H), 2.55(t, 1H), 2.74–2.79(m, 3H), 2.94–3.04(m, 1H), 3.56–3.66(m, 1H), 4.42(septet, 1H), 4.45–4.52(m, 1H), 6.98(dd, 2H), 7.02(d, 2H), 7.25(d, 1H), 7.35(t, 1H), 7.49(d, 1H), 7.58(d, 1H), 7.66(s, 1H) 302(I) (500.076MHz, DMSO-D6) δ 1.36(dq, 2H), 1.54–1.60(m, 2H), 1.72–1.75(m, 2H), 1.91(s, 3H), 1.91–1.95(m, 2H), 2.05(s, 3H), 2.39(t, 2H), 2.74–2.78(m, 2H), 2.80–2.87(m, 1H), 4.05–4.19(m, 2H), 4.42(septet, 1H), 5.22(s, 2H), 6.58(d, 1H), 6.97–6.99(m, 2H), 7.00(s, 1H), 7.25(d, 1H), 7.49(d, 1H) 303(I) (500.076MHz, DMSO-D6) δ 1.54–1.63(m, 4H), 1.69–1.82(m, 4H), 1.91–1.96(m, 2H), 1.91(s, 3H), 2.35–2.44(m, 2H), 2.73–3.04(m, 7H), 4.39–4.46(m, 2H), 6.48–6.49(m, 1H), 6.98(d, 1H), 7.02–7.07(m, 3H), 7.26(s, 1H), 7.34(t, 1H), 7.49(d, 1H), 7.62(d, 1H) 304(I) (500.076MHz, DMSO-D6) δ 1.33(t, 3H), 1.36–1.43(m, 2H), 1.54–1.60(m, 2H), 1.70–1.80(m, 2H), 1.91–1.96(m, 2H), 1.91(s, 3H), 2.39(t, 2H), 2.51–2.55(m, 1H), 2.74–2.79(m, 2H), 3.79(s, 3H), 4.01–4.05(m, 1H), 4.02(q, 2H), 4.42(septet, 1H), 4.47–4.53(m, 1H), 6.94(s, 2H), 6.97–6.99(m, 2H), 7.25(d, 1H), 7.49(d, 1H) 305(I) (500.076MHz, DMSO-D6) δ 1.37–1.46(m, 2H), 1.54–1.61(m, 2H), 1.67–1.83(m, 2H), 1.91–1.96(m, 2H), 1.91(s, 3H), 2.40(t, 2H), 2.53–2.58(m, 1H), 2.74–2.80(m, 2H), 2.99–3.10(m, 1H), 3.63–3.74(m, 1H), 4.42(septet, 1H), 4.46–4.54(m, 1H), 6.29–6.30(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.43–7.44(m, 1H), 7.48(t, 3H), 7.64(d, 2H) 306(I) (500.076MHz, DMSO-D6) δ 1.22–1.40(m, 2H), 1.54–1.61(m, 2H), 1.75(t, 2H), 1.91–1.96(m, 2H), 2.38(t, 2H), 2.53–2.60(m, 1H), 2.71–2.77(m, 2H), 3.03(t, 1H), 3.79(s, 2H), 3.98–4.03(m, 1H), 4.36–4.40(m, 1H), 4.40–4.45(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.50(d, 1H), 8.34(s, 1H), 8.40(s, 1H), 8.57(d, 1H) 307(I) (500.076MHz, DMSO-D6) δ 1.17–1.31(m, 2H), 1.53–1.59(m, 2H), 1.69(t, 2H), 1.88–1.94(m, 2H), 2.35(t, 2H), 2.45–2.52(m, 1H), 2.68–2.74(m, 2H), 2.95(t, 1H), 3.50(s, 2H), 3.59(s, 3H), 4.06–4.10(m, 1H), 4.36–4.43(m, 2H), 6.88(s, 1H), 6.97(dd, 1H), 7.25(d, 1H), 7.45(s, 1H), 7.49(d, 1H) 308(I) (500.076MHz, DMSO-D6) δ 1.03(dq, 1H), 1.18(dq, 1H), 1.49–1.58(m, 3H), 1.68(d, 1H), 1.83–1.90(m, 2H), 1.91(s, 3H), 2.23–2.30(m, 2H), 2.41–2.49(m, 3H), 2.57–2.67(m, 2H), 2.90(t, 1H), 3.66(q, 2H), 4.01(d, 1H), 4.38(septet, 1H), 4.43(d, 1H), 6.58(dd, 1H), 6.88(d, 1H), 6.96(dd, 1H), 7.07(d, 1H), 7.12(d, 1H), 7.23(d, 1H), 7.49(d, 1H), 8.58(s, 1H) 309(I) (500.076MHz, DMSO-D6) δ 1.46–1.56(m, 2H), 1.89–1.98(m, 2H), 2.03–2.18(m, 4H), 2.23(d, 1H), 2.55–2.61(m, 1H), 3.02–3.17(m, 4H), 3.42–3.51(m, 2H), 3.98(s, 2H), 4.16(d, 1H), 4.54(d, 1H), 4.60–4.66(m, 1H), 6.93–6.97(m, 1H), 7.01–7.09(m, 1H), 7.15(s, 1H), 7.25(s, 1H), 7.34–7.38(m, 1H), 7.54–7.58(m, 1H) 310(I) (500.076MHz, DMSO-D6) δ 1.11(t, 3H), 1.39–1.48(m, 2H), 1.55–1.60(m, 2H), 1.65–1.72(m, 1H), 1.81–1.87(m, 1H), 1.90–1.95(m, 2H), 1.90(s, 3H), 2.39(t, 2H), 2.53–2.59(m, 1H), 2.74–2.83(m, 2H), 3.03–3.10(m, 1H), 3.36(q, 2H), 3.47–3.55(m, 1H), 4.42(septet, 1H), 4.46–4.54(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H), 7.72–7.78(m, 2H), 7.86(s, 1H), 7.96(d, 1H) 311(I) (500.076MHz, DMSO-D6) δ 0.92(t, 3H), 1.40–1.49(m, 2H), 1.55–1.64(m, 2H), 1.57(sextet, 2H), 1.65–1.73(m, 1H), 1.81–1.88(m, 1H), 1.91(s, 3H), 1.91–1.96(m, 2H), 2.36–2.44(m, 2H), 2.54–2.61(m, 1H), 2.73–2.84(m, 2H), 3.02–3.11(m, 1H), 3.45–3.53(m, 1H), 4.40–4.46(m, 1H), 4.50–4.54(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H), 7.72–7.78(m, 2H), 7.86(s, 1H), 7.96(d, 1H) 312(I) (500.076MHz, DMSO-D6) δ 0.98(d, 6H), 1.39–1.49(m, 2H), 1.54–1.61(m, 2H), 1.64–1.71(m, 1H), 1.81–1.87(m, 1H), 1.90–1.95(m, 2H), 1.91(s, 3H), 2.02(septet, 1H), 2.39(t, 2H), 2.53–2.59(m, 1H), 2.74–2.79(m, 2H), 3.03–3.11(m, 1H), 3.45–3.52(m, 1H), 4.42(septet, 1H), 4.47–4.53(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H), 7.71–7.77(m, 2H), 7.88(s, 1H), 7.98(d, 1H) 313(I) (500.076MHz, DMSO-D6) δ 1.41–1.53(m, 2H), 1.54–1.62(m, 2H), 1.66–1.74(m, 1H), 1.84–1.89(m, 1H), 1.91–1.96(m, 2H), 1.91(s, 3H), 2.36–2.44(m, 2H), 2.54–2.62(m, 1H), 2.73–2.87(m, 4H), 3.10(t, 1H), 3.50(s, 3H), 3.52(s, 3H), 3.52–3.58(m, 1H), 4.40–4.46(m, 1H), 4.48–4.54(m, 1H), 6.97–7.00(m, 1H), 7.23–7.29(m, 1H), 7.50(d, 1H), 8.06(d, 1H), 8.16(s, 1H), 8.29(d, 1H) 314(I) (500.076MHz, DMSO-D6) δ 1.34(t, 3H), 1.35–1.41(m, 2H), 1.54–1.60(m, 2H), 1.74(d, 2H), 1.90–1.96(m, 2H), 1.90(s, 3H), 2.39(t, 2H), 2.50–2.55(m, 1H), 2.73–2.79(m, 2H), 2.80–2.89(m, 1H), 4.01(q, 2H), 4.08–4.19(m, 2H), 4.42(septet, 2H), 5.06(s, 2H), 6.62(d, 1H), 6.77(d, 1H), 6.81(s, 2H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H) 315(I) (DMSO-D6) δ 1.53–1.82(m, 2H), 2.02–2.36(m, 5H), 2.60–2.67(m, 1H), 3.07–3.15(m, 2H), 3.31–3.38(m, 1H), 3.43–3.53(m, 2H), 4.12–4.19(m, 4H), 4.51(d, 1H), 4.68(septet, 1H), 4.85(s, 1H), 7.06(ddd, 1H), 7.37(dd, 1H), 7.56(t, 1H), 7.94(d, 2H), 8.86(d, 2H), 11.47(s, 1H) 316(I) (DMSO-D6) δ 1.58–2.28(m, 4H), 2.67–2.84(m, 1H), 2.91–3.04(m, 2H), 2.97(s, 2H), 3.06–3.26(m, 2H), 3.24–3.42(m, 1H), 3.44–3.67(m, 3H), 3.57(s, 3H), 4.55–4.77(m, 2H), 4.83(s, 1H), 7.00–7.09(m, 2H), 7.35–7.58(m, 5H) 317(I) (DMSO-D6) δ 1.52(dq, 2H), 1.74–1.92(m, 2H), 1.93–2.04(m, 4H), 2.42–2.50(m, 2H), 2.55(tt, 1H), 2.77–2.85(m, 2H), 2.87–2.96(m, 2H), 4.22–4.30(m, 3H), 6.69–6.74(m, 2H), 6.76(d, 1H), 6.99(d, 1H), 7.07(dd, 1H), 7.16(dt, 1H), 7.29(s, 2H), 7.32(s, 1H) 318(I) (DMSO-D6) δ 1.71(m, 2H), 2.18(m, 3H), 2.70(s, 3H), 3.02(m, 1H), 3.15(m, 2H), 3.32(m, 3H), 3.50(m, 2H), 4.63(m, 1H), 7.05(ddd, 1H), 7.36(m, 4H), 7.56(t, 1H), 7.66(d, 1H), 8.11(s, 1H), 8.37(d, 1H) 319(I) (DMSO-D6) δ 1.40(m, 2H), 1.57(m, 2H), 1.79(m, 2H), 1.90(m, 2H), 2.40(m, 2H), 2.58(m, 1H), 2.79(m, 2H), 2.87(m, 2H), 4.30(d, 2H), 4.43(m, 1H), 6.97(dd, 1H), 7.13(m, 2H), 7.25(d, 1H), 7.43(d, 1H), 7.49(d, 1H), 7.65(m, 2H) 321(I) (DMSO-D6) δ 1.67–1.78(m, 2H), 1.95–2.09(m, 3H), 2.18–2.27(m, 2H), 2.44(d, 3H), 2.77–2.88(m, 1H), 3.08–3.19(m, 3H), 3.33–3.52(m, 5H), 3.59–3.67(m, 1H), 4.60–4.68(m, 1H), 4.84(s, 1H), 7.05(ddd, 1H), 7.14–7.27(m, 1H), 7.37(dd, 1H), 7.55(t, 1H), 7.61(q, 1H), 7.70–7.71(m, 2H), 7.78–7.80(m, 1H), 7.86–7.89(m, 1H) 322(I) (DMSO-D6) δ 1.65–1.80(m, 2H), 1.99–2.09(m, 2H), 2.19–2.30(m, 3H), 2.77–2.90(m, 1H), 3.07–3.21(m, 3H), 3.30–3.37(m, 3H), 3.47–3.57(m, 2H), 3.59–3.71(m, 1H), 4.59–4.69(m, 1H), 4.82–4.86(m, 1H), 7.05(ddd, 1H), 7.37(dd, 1H), 7.49(s, 2H), 7.55(t, 1H), 7.64–7.69(m, 2H), 7.84–7.86(m, 1H), 7.92(td, 1H) 323(I) (DMSO-D6) δ 1.64–1.78(m, 2H), 1.99–2.09(m, 2H), 2.17–2.29(m, 3H), 2.70–2.85(m, 1H), 3.04–3.19(m, 3H), 3.28–3.38(m, 3H), 3.31(s, 3H), 3.46–3.55(m, 2H), 3.66(t, 2H), 4.12(t, 2H), 4.56–4.68(m, 1H), 4.81–4.86(m, 1H), 6.94–6.97(m, 2H), 7.04(dd, 1H), 7.05(ddd, 1H), 7.34–7.39(m, 2H), 7.55(t, 1H) 324(I) (CDCl₃) δ 1.45(s, 9H), 1.48–1.67(m, 4H), 1.75–1.85(m, 2H), 1.90–2.03(m, 3H), 2.42–2.51(m, 2H), 2.56(m, 1H), 2.71–2.84(m, 3H), 2.91–3.06(m, 1H), 3.54(q, 2H), 3.75–3.88(m, 1H), 4.03(t, 2H), 4.27(septet, 1H), 4.68–4.82(m, 1H), 4.93–5.01(m, 1H), 6.75(dd, 1H), 6.90–7.00(m, 3H), 7.25–7.32(m, 3H) 325(I) (DMSO-D6) δ 1.70–1.84(m, 2H), 2.00–2.09(m, 2H), 2.20–2.29(m, 3H), 2.81–2.91(m, 1H), 3.09–3.21(m, 3H), 3.28–3.38(m, 3H), 3.48–3.57(m, 2H), 3.61–3.70(m, 1H), 4.61–4.72(m, 1H), 4.82–4.86(m, 1H), 7.05(ddd, 1H), 7.14–7.27(m, 1H), 7.37(dd, 1H), 7.56(t, 1H), 7.76–7.79(m, 1H), 8.51(s, 1H), 8.80(d, 1H) 326(I) (DMSO-D6) δ 1.70–1.78(m, 2H), 2.00–2.09(m, 2H), 2.18–2.26(m, 2H), 3.05–3.17(m, 2H), 3.24–3.40(m, 2H), 3.97–4.06(m, 2H), 4.44–4.52(m, 2H), 4.59–4.70(m, 2H), 4.73(s, 2H), 4.81–4.86(m, 1H), 4.91–4.93(m, 2H), 6.90–6.93(m, 1H), 6.96–7.04(m, 1H), 7.07–7.11(m, 1H), 7.17–7.20(m, 1H), 7.34–7.43(m, 2H), 7.52–7.55(m, 1H) 327(I) (CDCl₃) δ 1.52–1.63(m, 4H), 1.77–1.86(m, 2H), 1.92–2.03(m, 4H), 2.44–2.50(m, 2H), 2.58–2.67(m, 1H), 2.77–2.83(m, 2H), 3.05(bs, 1H), 3.36(s, 3H), 4.26–4.31(m, 2H), 6.74–6.77(m, 1H), 6.99–7.01(m, 1H), 7.30–7.33(m, 1H), 7.47(s, 1H) 328(I) (CDCl₃) δ 1.43–1.67(m, 4H), 1.73–1.91(m, 4H), 1.95–2.02(m, 2H), 2.42–2.50(m, 2H), 2.52–2.62(m, 1H), 2.77–2.85(m, 2H), 2.92(bs, 2H), 3.06(s, 3H), 4.23–4.30(m, 1H), 5.26(s, 2H), 6.73–6.79(m, 2H), 6.99–7.00(m, 1H), 7.29–7.32(m, 1H), 7.47–7.50(m, 1H), 7.82–7.82(m, 1H) 329(I) (CDCl₃) δ 1.50–1.69(m, 4H), 1.77–1.86(m, 2H), 1.92–2.02(m, 4H), 2.45–2.49(m, 2H), 2.59–2.65(m, 1H), 2.79–2.83(m, 2H), 3.02(bs, 1H), 3.39(s, 3H), 4.26–4.30(m, 2H), 5.88(bs, 1H), 6.74–6.77(m, 1H), 6.99–7.00(m, 1H), 7.30–7.32(m, 1H), 7.46(bs, 1H), 7.65(s, 1H) 330(I) (DMSO-D6) δ 1.73–3.63(m, 17H), 4.57–4.70(m, 1H), 7.01–7.88(m, 7H) 331(I) (DMSO-D6) δ 1.21(d, 6H), 1.37–2.03(m, 8H), 2.33–3.42(m, 7H), 4.15–4.19(m, 1H), 4.37–4.45(m, 1H), 5.89(s, 2H), 6.96–8.34(m, 4H) 332(I) (DMSO-D6) δ 1.41–1.94(m, 8H), 2.37–2.78(m, 8H), 3.32(s, 3H), 4.38–4.46(m, 1H), 6.96–7.78(m, 5H) 333(I) (CDCl₃) δ 1.80–1.96(m, 5H), 2.38(s, 4H), 2.41–3.00(m, 12H), 3.57–3.60(m, 1H), 4.26(s, 1H), 4.73–4.76(m, 1H), 6.73–7.32(m, 3H) 334(I) (DMSO-D6) δ 1.33–1.93(m, 8H), 2.33–3.27(m, 7H), 4.39–4.45(m, 1H), 4.49–4.53(m, 1H), 6.96–8.98(m, 5H) 335(I) (CDCl₃) δ 1.16–1.30(m, 1H), 1.33–1.48(m, 1H), 1.76–2.75(m, 12H), 2.96–3.05(m, 1H), 3.72(s, 2H), 3.89–3.93(m, 1H), 4.21–4.30(m, 1H), 4.66–4.71(m, 1H), 6.72–7.32(m, 7H) 336(I) (DMSO-D6) δ 1.37–2.83(m, 17H), 4.38–4.47(m, 1H), 5.76(s, 1H), 6.96–7.96(m, 6H) 337(I) (DMSO-D6) δ 1.33–1.99(m, 8H), 2.36–2.60(m, 4H), 2.73–2.82(m, 2H), 2.94(s, 3H), 2.98–3.09(m, 1H), 3.55–3.66(m, 1H), 4.38–4.46(m, 1H), 4.56(s, 2H), 6.96–7.00(m, 1H), 7.23–7.27(m, 1H), 7.41–7.52(m, 5H) 338(I) (DMSO-D6) δ 1.35–1.99(m, 8H), 2.37–2.46(m, 2H), 2.55–2.63(m, 2H), 2.73–2.85(m, 2H), 2.92(s, 3H), 2.97–3.06(m, 1H), 3.55–3.65(m, 1H), 4.41–4.49(m, 1H), 4.56(s, 2H), 6.96–7.01(m, 1H), 7.25–7.27(m, 1H), 7.39–7.52(m, 5H)  1(III) δ (DMSO-D6) 1.57–1.36(2H, m), 2.25–1.87(5H, m), 2.45–2.33(2H, m), 3.16–2.97(2H, m), 3.37–3.17(4H, m), 3.45–3.40(1H, m), 4.12(0H, t), 4.53(1H, d), 4.67–4.58(1H, m), 4.84–4.77(1H, m), 5.45(1H, d), 7.03(1H, ddd), 7.19(2H, t), 7.42–7.33(3H, m), 7.55(1H, m), 10.59–10.38(1H, m)  2(III) δ (DMSO-D6) 1.60–1.36(2H, m), 2.27–1.93(5H, m), 2.61–2.57(1H, m), 2.90–2.73(1H, m), 3.13–2.94(2H, m), 3.41–3.23(3H, m), 4.17–3.85(2H, m), 4.68–4.47(2H, m), 4.84–4.77(1H, m), 5.43(1H, d), 7.09–6.99(1H, m), 7.40–7.27(6H, m), 7.55(1H, t), 11.13–10.92(1H, m)  3(III) δ (DMSO-D6) 1.27–1.07(1H, m), 1.57–1.36(1H, m), 2.24–1.89(5H, m), 2.66–2.56(1H, m), 2.93–2.79(1H, m), 3.16–3.00(2H, m), 3.51–3.39(2H, m), 4.18(1H, t), 4.67–4.46(2H, m), 4.84–4.78(1H, m), 5.51–5.43(1H, m), 6.05(1H, s), 7.04(1H, dd), 7.24–7.17(1H, m), 7.48–7.33(3H, m), 7.55(1H, dd), 10.41–10.23(1H, m)

TABLE VII Com- pound MP (Table) MS (° C.) ¹H NMR Can be prepared using:  3(IV) 495 181–182 (DMSO-D6) δ 1.2–2.8(bm, 14H), 3.1(bm, 1H), 3.35(s, 3H), 3.5(bm, Example 12 (M+H) 1H), 4.4(m, 1H), 4.5(bm, 1H), 6.82(dd, 1H), 7.1(dd, 1H), 7.4(t, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)  2(IV) 495 111–112 (DMSO-D6) δ 1.6–2.3(bm, 8H), 3.0–3.6(bm, 8H), 3.3(s, 3H), 4.5–4.8(m, 2H), Example 12 and final (M+H) 6.9–7.1(m, 1H), 7.2–7.4(m, 2H), 7.8(m, 2H), 7.94(d, 1H), product isolated as 8.03(d, 1H), 10.9(bm, 1H) Hydrochloride by treatment with a solution of HCl in dioxan and evaporation.  7(IV) 459 149–150 (DMSO-D6) δ 1.2–3.7(bm, 16H), 3.75(s, 3H), 3.85(bm, 1H), 4.6(bm, As for 2(IV) above (M+H) 1H), 5.05(bm, 1H), 6.9(m, 4H), 7.78(m, 2H), 7.92(d, 1H), 8.05(m, 1H), 11.0 and 11.8(bm, 1H)  8(IV) 463 126–127 (DMSO-D6) δ 1.2–3.6(bm, 16H), 3.9(bm, 1H), 4.6 bm, 1H), 5.14 As for 2(IV) above (M+H) (bm, 1H), 7.0(d, 2H), 7.38(d, 2H), 7.75(m, 2H), 7.9(m, 1H), 8.05(m, 1H), 11.3 and 11.95(bm, 1H)  9(IV) 497 78–80 (DMSO-D6) δ 1.2–4.0(bm, 17H), 4.6(bm, 1H), 5.2(bm, 1H), 7.0(dd, As for 2(IV) above (M+H) 1H), 7.3(m, 1H), 7.58(d, 1H), 7.78(d, 2H), 7.95(d, 1H), 8.05(m, 1H)11.0 and 11.65(bm, 1H)  10(IV) 454 78–80 (DMSO-D6) δ 1.2–3.6(m, 17H), 4.25(bm, 1H), 4.98(m, 1H), 7.03(d, Example 12 (M+H) 2H), 7.72(m, 4H), 7.9(s, 1H), 8.0(m, 1H)  11(IV) 465 82–83 (DMSO-D6) 1.2–3.4(m, 16H), 3.5(bm, 1H), 4.3(bm, 1H), 4.85(m, Example 12 (M+H) 1H), 6.7(m, 1H), 7.0(m, 1H), 7.3(q, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.0(m, 1H)  12(IV) 447 64–65 (DMSO-D6) δ 1.2–3.3(m, 16H), 3.45(bm, 1H), 4.25(m, 1H), 4.8(m, Example 12 (M+H) 1H), 6.9(m, 2H), 7.1(t, 2H), 7.75(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)  13(IV) 500 110–111 (DMSO-D6) δ 1.2–4.8(bm, 24H), 6.95(dd, 2H), 7.5(m, 2H), 7.8(m, As for 2(IV) above (M+H) 2H), 7.95(s, 1H), 8.02(d. 1H), 9.85(d, 1H), 10.7(bm, 1H)  14(IV) 457 140–142 (DMSO-D6) δ 1.2–4.8(m, 24H), 6.86(bm, 2H), 7.02(m, 2H), 7.75 Example 12 (M+H) (bm, 2H), 7.90(s, 1H), 8.03(bm, 1H)  15(IV) 491 94–95 (DMSO-D6) δ 1.2–4.8(bm, 24 H). 6.8(bd, 1H), 7.0(bs, 1H), 7.3(d, Example 12 (M+H) 1H), 7.75(m, 2H), 7.9(s, 1H), 8.0(m, 1H)  16(IV) 477 150–152 (DMSO-D6) δ 1.2–4.6(bm, 21H), 7.0(bm, 2H), 7.3(bm, 2H), 7.75(m, 2H), Example 12. (M+H) 7.9(s, 1H), 8.0(m, 1H)  17(IV) 461 219–220 (DMSO-D6) δ 1.2–4.8(bm, 21 H), 6.9–7.3(m, 4H), 7.75(m, 2H), 7.92 As for 2(IV) above (M+H) (s, 1h), 8.02(m, 1H).  18(IV) 511 104–105 (DMSO-D6) δ 1.2–5.0(bm, 21H), 7.3(d, 1H) 7.4(dd, 1H), 7.6(dd, Example 12 and final (M+H) 1H), 7.75(m, 2H), 7.95(s, 1H), 8.0(d, 1H), 9.5 and 9.7(bs, 1H) product isolated as trifluoroacetate by evaporation of Reverse Phase HPLC fractions.  19(IV) 495 76–77 (DMSO-D6) δ 1.2–5.0(bm, 21H), 7.2(m, 1H), 7.3(m, 1H), 7.45(m, As for 18(IV) above (M+H) 1H), 7.75(m, 2H), 7.95(s, 1H), 8.05(m, 1H), 9.5(bm, 1H)  20(IV) 479 230–232 (DMSO-D6) δ 1.2–3.7(bm, 19H), 4.4–4.7(bm, 2H), 7.02(t, 1H), 7.3(m, 2H), As for 2(IV) above (M+H) 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H)  21(IV) 495 69–70 (DMSO-D6) 1.2–4.0(m, 19 H), 4.4–4.8(m, 2H), 7.3(m, 2H), 7.5(m, As for 18(IV) above (M+H) 1H), 7.75(m, 2H), 7.98(s, 1H), 8.0(m, 1H), 9.5(bm, 1H)  22(IV) 475 130–132 (CDCl₃) δ 1.0–3.6(m, 19H), 3.7(s, 3H), 4.6(m, 2H), 6.6–6.9(m, 3H), As for 2(IV) above (M+H) 7.7(m, 2H), 8.0(m, 2H)  24(IV) 462 72–73 (DMSO-D6) 1.6(m, 2H), 1.8(m, 1H), 2.01(m, 4H), 2.3(m, 1H), 2.55(m, 2H), Example 13 (M+H) 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), 3.58(m, 2H), 3.8(s, 3H), 4.3(bs, 2H), 4.6 and 4.8(m, 1H), 6.7(d, 1H), 6.8–7.0(m, 3H), 7.2(m, 1H), 7.5(m, 1H), 9.5(bs, 1H)  26(IV) 458 111–112 (DMSO-D6) δ 1.4–3.6(m, 17H), 3.8(2s, 6H), 4.2–4.5(m, 3H), 6.7(m, Example 13 (M+H) 2H), 6.82(m, 2H), 6.9–7.2(m, 2H)  27(IV) 440 73–75 (DMSO-D6) δ 1.6–1.9(m, 3H), 2.0–2.3(m, 2H), 2.4–2.6(m, 2H), 2.9(m, 2H), Example 13 (M+H) 3.18(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.7(s, 3H), 3.8(s, 3H), 4.2(bs, 2H), 4.4 and 4.6(2m, 1H), 6.7(d, 1H), 6.9(m, 5H), 7.0 (d, 1H), 9.7(bm, 1H)  28(IV) 462 81–83 (DMSO-D6) δ 1.6(m, 2H), 1.8(m, 1H), 2.05(m, 4H), 2.3(m, 1H), 2.5(m, 1H), Example 13 (M+H) 2.9(m, 2H), 3.2(m, 2H), 3.3(m, 2H), 3.4(m, 1H), 3.55(m, 2H), 3.8(s, 3H), 4.3(bs, 2H), 4.6 and 4.8(m, 1H), 6.62(d, 1H), 6.81 (d, 1H), 6.9(s, 1H), 7.05(m, 1H), 7.35(m, 2H), 9.76(bm, 1H)  29(IV) 424 97–99 (DMSO-D6) δ 1.4–2.6(m, 14H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), Example 13 (M+H) 3.55(m, 2H), 3.8(s, 3H), 4.3(bs, 2H), 4.5 and 4.7(m, 1H), 6.65(d, 1H), 6.9(m, 4H), 7.1(m, 1H), 9.5(bs, 1H)  30(IV) 458 78–79 (DMSO-D6) δ 1.5–2.6(m, 13H), 2.3(s, 3H), 2.9(m, 2H), 3.2(m, 2H), Example 13 (M+H) 3.4(m, 1H), 3.55(m, 2H), 4.3(bs, 2H), 4.55 and 4.75(m, 1H), 6.67 (d, 1H), 6.85(m, 3H), 7.0(dd, 1H), 7.32(t, 1H), 9.5(bs, 1H)  31(IV) 444 100–101 (DMSO-D6) δ 1.6(m, 2H), 1.8(m, 1H), 2.0(m, 4H), 2.3(m, 1H), 2.5(m, 2H), Example 13 (M+H) 2.9(m, 2H), 3.18(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.8(s, 3H), 4.2(bs, 2H), 4.6 and 4.8(m, 1H), 6.62(d, 1H), 6.8(m, 2H), 7.0(m, 2H), 7.36(m, 2H), 9.7(bs, 1H)  32(IV) 428 74–75 (DMSO-D6) 1.6(m, 2H), 1.8(m, 1H), 2.0(m, 4H), 2.3(m, 1H), 2.5(m, 2H), Example 13 (M+H) 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.8(s, 3H), 4.2(bs, 2H), 4.5 and 4.7(m, 1H), 6.7(d, 1H), 6.85(d, 1H), 6.9(s, 1H), 7.02(m, 1H), 7.04(m, 1H), 7.18(m, 2H), 9.6(m, 1H)  33(IV) 478 117–119 (DMSO-D6) δ 1.6–3.6(m, 17H), 3.8(s, 3H), 4.25(bs, 2H), 4.6 and 4.9(m, 1H), Example 13 (M+H) 6.6(d, 1H), 6.8(m, 2H), 7.3(m, 1H), 7.4(m, 1H), 7.6(m, 1H), 9.5(bs, 1H)  34(IV) 462 109–110 (DMSO-D6) δ 1.6–3.6(m, 17H), 3.8(s, 3H), 4.25(bs, 2H), 4.55 and Example 13 (M+H) 4.85(m, 1H), 6.6(d, 1H), 6.8(m, 2H), 7.2(m, 1H), 7.3(m, 1H), 7.45(m, 1H), 9.5(bs, 1H)  37(IV) 442 89–90 (DMSO-D6) δ 1.6–3.6(m, 20H), 3.8(s, 3H), 4.25(bs, 2H), 4.45 and Example 13 (M+H) 4.75(m, 1H), 6.6(d, 1H), 6.8(m, 2H), 7.0(m, 3H), 9.6(bs, 1H)  38(IV) 471 143–145 (DMSO-D6) δ 1.6–3.6(m, 19H), 4.2–4.8(m, 2H), 7.0(m, 1H), 7.2(d, As for 18(IV) above (M+H) 1H), 7.22(s, 1H), 7.8(d, 1H), 8.5(d, 1H), 8.8(s, 1H)  39(IV) 475 141–142 (DMSO-D6) δ 1.6–3.6(m, 16H), 4.2–4.8(m, 2H), 6.9(m, 1H), 7.2(m, As for 18(IV) above (M+H) 1H), 7.5(m, 1H), 7.8(d, 1H), 8.5(d, 1H), 8.8(d, 1H)  41(IV) 471 160–162 (DMSO-D6) δ 1.6–3.6(m, 16H), 3.8(s, 3H), 4.2–4.8(m, 2H), 6.7(m, As for 18(IV) above (M+H) 1H) 6.9–7.2(m, 2H), 7.8(d, 1H), 8.5(d, 1H), 8.8(d, 1H)  42(IV) 453 116–118 (DMSO-D6) δ 1.6–3.6(m, 16H), 3.7(s, 3H), 4.2–4.8(m, 2H), 6.8–7.1(m, 3H), As for 18(IV) above (M+H) 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H), 9.6(bs, 1H)  43(IV) 475 109–110 (DMSO-D6) δ 1.6–3.6(m, 16H), 4.2–4.8(m, 2H), 7.07(m, 1H), 7.35(m, 2H), As for 18(IV) above (M+H) 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H), 9.6(bs, 1H)  44(IV) 437 136–137 (DMSO-D6) δ 1.6–3.2(m, 15H), 3.3(s, 3H), 3.6(m, 1H), 4.22(m, Example 12 (M+H) 1H), 4.5(m, 1H), 6.8(d, 2H), 7.10(d, 2H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H)  89(IV) 471 100–102 (DMSO-D6) δ 1.0–4.2(m, 21H), 6.0(m, 1H), 6.18(m, 1H), 6.42(m, As for 18(IV) above (M+H) 1H), 7.02(d, 1H), 7.6(d, 1H), 7.85(d, 1H)  47(IV) 441 133–136 (DMSO-D6) δ 1.6–4.8(m, 18H), 6.9–7.2(m, 4H), 7.82(d, 1H), 8.52(d, As for 18(IV) above (M+H) 1H), 8.8(d, 1H)  48(IV) 491 105–106 (DMSO-D6) δ 1.6–4.8(m, 18H), 6.3(d, 1H), 6.4(d, 1H), 6.58(s, 1H), As for 18(IV) above (M+H) 6.9(d, 1H), 7.52(d, 1H), 7.8(d, 1H)  49(IV) 475 123–125 (DMSO-D6) δ 1.6–4.8(m, 18H), 7.2(m, 1H), 7.3(m, 1H), 7.45(m, As for 18(IV) above (M+H) 1H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H)  50(IV) 459 93–94 (DMSO-D6) δ 1.6–4.8(m, 18H), 7.05(m, 1H), 7.3(m, 2H), 7.82(d, As for 18(IV) above (M+H) 1H), 8.52(d, 1H), 8.8(d, 1H), 9.7(bm, 1H) 271(IV) 507 102–103 (DMSO-D6) δ 1.6–3.8(m, 16H), 3.3(s, 3H), 3.8(d, 3H), 4.4–4.7(m, Example 12 (M+H) 2H), 6.95(m, 1H), 7.1(m, 2H), 7.78(m, 2H), 7.95(s, 1H), 8.03(d, 1H) 272(IV) 505 97–98 (DMSO-D6) δ 1.6–4.8(m, 27H), 7.1(s, 2H), 7.6(m, 2H), 7.95(s, 1H), As for 18(IV) above (M+H) 8.03(d, 1H) 273(IV) 511 110–112 (DMSO-D6) δ 1.4–3.8(m, 16H), 3.3(s, 3H), 4.4–5.0(m, 2H), 7.22(m, As for 18(IV) above (M+H) 2H), 7.3(m, 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H) 274(IV) 511 114–115 (DMSO-D6) δ 1.4–3.8(m, 16H), 3.3(s, 3H), 4.4–5.0(m, 2H), 7.02(m, Example 12 (M+H) 1H), 7.4(m, 2H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H) 275(IV) 491 88–89 (DMSO-D6) δ 1.4–3.8(m, 16H), 2.25(s, 3H), 3.3(s, 3H), 4.2–4.8(m, Example 12 (M+H) 2H), 7.02(m, 2H), 7.22(m, 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H) 276(IV) 491 182–183 (DMSO-D6) δ 1.4–3.8(m, 16H), 2.25(s, 3H), 3.3(s, 3H), 4.4–4.6(m, Example 12 (M+H) 2H), 6.74(d, 1H), 7.02(s, 1H), 7.22(d, 1H), 7.75(m, 2H), 7.90(s, 1H), 8.0(d, 1H) 277(IV) 499 162–164 (DMSO-D6) δ 1.6–3.8(m, 19H), 2.25(s, 3H), 3.3(s, 3H), 4.5–5.0(m, As for 2(IV) above (M+H) 2H), 7.14(t, 1H), 7.8(m, 4H), 7.95(m, 1H), 8.02(d, 1H), 10.9(bm, 1H) 278(IV) 528 120–122 (DMSO-D6) δ 1.5–5.0(m, 29H), 6.9–7.2(m, 4H), 7.75(m, 2H), 7.95 As for 2(IV) above (M+H) (s, 1H), 8.02(d, 1H), 10.2(bs, 1H), 11.0–11.3(bm, 1H) 279(IV) 505 97–99 (DMSO-D6) δ 1.18(t, 3H), 1.6–3.7(m, 17H), 2.62(q, 2H), 3.3(s, 3H), Example 12 (M+H) 4.4–4.8(m, 1H), 6.8–7.1(m, 2H), 7.3(m, 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(m, 1H), 9.4(bs, 1H) 280(IV) 494 138–140 (DMSO-D6) δ 1.8(m, 2H), 2.1–4.4(m, 14H), 3.3(s, 3H), 4.62(bm, As for 2(IV) above (M+H) 1H), 4.9 and 5.1(m, 1H), 7.65(m, 1H), 7.8(m, 2H), 7.85(m, 2H), 7.95 (d, 1H), 8.01(d, 1H), 8.3(t, 1H), 9.0(t, 1H), 9.15(t, 1H), 10.35(bs, 1H), 11.5(bs, 1H) 281(IV) 499 98–99 (DMSO-D6) δ 1.2(s, 9H), 1.3–3.6(m, 20H), 4.5(m, 1H), 6.8(t, 1H), Example 12 (M+H) 6.9(d, 1H), 7.1(t, 1H), 7.2(d, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.0(d, 1H) 282(IV) 483 79–80 (DMSO-D6) δ 1.2–3.6(m, 22H), 3.3(s, 3H), 4.22 and 4.5(m, 2H), Example 12 (M+H) 6.67(d, 1H), 6.8(s, 1H), 7.08(d, 1H), 7.75(m, 2H), 7.9(s, 1H), 8.0(d, 1H) 283(IV) 559 113–115 (DMSO-D6) δ 1–1.48(m, 29H), 3.3(s, 3H), 7.0(m, 1H), 7.18(m, 2H), Example 12 (M+H) 7.75(m, 2H), 7.9(s, 1H), 8.0(m, 1H) 284(IV) 520 111–112 (DMSO-D6) δ 1.6–4.0(m, 19H), 4.6 and 4.9(m, 2H), 7.2(m, 1H), As for 18(IV) above (M+H) 7.4–7.8(m, 6H), 7.95(s, 1H), 8.02(d, 1H), 9.5(bm, 1H) 285(IV) 544 111–112 (DMSO-D6) δ 1.6–3.2(m, 15H), 3.3(s, 3H), 3.5(m, 1H), 4.5 and 4.6(m, 2H), Example 12 (M+H) 6.9(d, 1H), 7.35(d, 1H), 7.5(dd, 1H), 7.75(m, 2H), 7.81(d, 1H), 7.9(s, 1H), 8.0(dd, 1H), 8.68(d, 1H) 286(IV) 491 115–117 (DMSO-D6) δ 1.6–3.2(m, 16H), 3.3(s, 3H), 3.35–3.6(m, 3H), 4.4–4.9(m, 2H), Example 12 (M+H) 6.9(m, 1H), 7.0–7.2(m, 2H), 7.75(m, 2H), 7.92(s, 1H), 8.02(m, 1H) 287(IV) 443 142–144 (DMSO-D6) δ 1.6–3.4(m, 14H), 3.3(s, 3H), 3.4–3.7(m, 2H), 4.6–4.8(m, 2H), Example 12 (M+H) 7.0(m, 3H), 7.3(m, 2H), 7.75(m, 2H), 7.92(s, 1H), 8.04(dd, 1H) 288(IV) 525 84–86 (DMSO-D6) δ 1.6–3.4(m, 22H), 4.2–4.7(m, 2H), 7.38(d, 1H), 7.5(d, As for 18(IV) above (M+H) 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(m, 1H) 289(IV) 491 149–151 (DMSO-D6) δ 1.3–2.0(m, 8H), 2.22(s, 3H), 2.3–2.6(m, 4H), 2.8(m, Example 12 (M+H) 2H), 3.1(m, 1H), 3.3(s, 3H), 3.5(m, 1H), 4.3–4.6(m, 2H), 6.84(dd, 1H), 7.0(d, 1H), 7.2(m, 1H), 7.75(m, 2H), 7.9(s, 1H), 8.0(dd, 1H) 290(IV) 502 93–95 (DMSO-D6) δ 1.6–4.0(m, 16H), 3.3(s, 3H), 4.4–5.1(m, 2H), 7.4(t, As for 18(IV) above (M+H) 1H), 7.8(m, 3H), 7.9–8.1(m, 3H), 9.5–10.0(bm, 1H) 293(IV) 445 66–68 (DMSO-D6) δ 1.6–3.0(m, 7H), 2.8(m, 1H), 3.2(m, 3H), 3.3(s, 3H), Example 15 (M+H) 3.4–3.7(m, 4H), 4.62(m, 1H), 5.1–5.4(m, 2H), 7.2(m, 1H), 7.8(m, 2H), 7.95(m, 1H), 8.02(d, 1H), 8.6(m, 2H), 9.5(bs, 1H) 339(I) (M+H) foam (DMSO-D6) δ 1.42–1.70(m, 5H), 1.84–1.94(m, 3H), 2.35–2.42(m, 2H), Example 2 step c 458 2.54–2.62(m, 1H), 2.73–2.87(m, 3H), 3.02–3.10(m, 1H), 3.30–3.36(m, 1H), 4.39–4.44(m, 1H), 4.53–4.57(m, 1H), 6.95–6.99(m, 1H), 7.24–7.25(m, 1H), 7.47–7.50(m, 1H), 7.56–7.67(m, 2H), 7.77–7.82(m, 1H), 7.94–7.96(m, 1H) 340(I) (M+H) 156–157 (DMSO-D6) δ 1.40–1.99(m, 8H), 2.35–2.46(m, 2H), 2.54–2.62(m, 1H), Example 2 step c 484 2.73–2.85(m, 3H), 3.02–3.13(m, 1H), 3.60–3.72(m, 1H), 4.39–4.47(m, 1H), 4.51–4.64(m, 1H), 6.96–7.00(m, 1H), 7.25–7.26(m, 1H), 7.50(d, 1H), 7.59–7.63(m, 1H), 7.74–7.78(m, 1H), 8.06–8.09(m, 2H), 8.45–8.48(m, 1H), 8.96–8.98(m, 1H) 341(I) (M+H) 127–129 (DMSO-D6) δ 1.44–1.99(m, 8H), 2.40–2.48(m, 2H), 2.58–2.67(m, 1H), Example 2 step c using 485 2.75–2.90(m, 3H), 3.04–3.16(m, 1H), 3.56–3.69(m, 1H), Quinoxaline-6- 4.40–4.49(m, 1H), 4.53–4.63(m, 1H), 6.96–7.00(m, 1H), 7.26–7.27(m, 1H), carboxylic acid 7.48–7.51(m, 1H), 7.85–7.88(m, 1H), 8.09–8.11(m, (obtained from 1H), 8.16–8.19(m, 1H), 9.01(s, 2H) hydrolysis of the commercially available Quinoxaline-6- carboxylic acid methyl ester) 342(I) (M+H) foam (DMSO-D6) δ 1.36–1.44(2H, m), 1.55–1.61(2H, m), 1.76–1.82 Example 2 step c using 532 (2H, m), 1.89–1.96(2H, m), 2.34–2.41(3H, m), 2.72–2.80(2H, m), 3-Amino-4- 2.95(2H, t), 3.21(3H, s), 4.15–4.22(2H, m), 4.38–4.46(1H, m), 5.87 methanesulfonyl- (2H, s), 6.96–6.99(2H, m), 7.24–7.26(2H, m), 7.49(1H, d), 8.34 thiophene-2-carboxylic (1H, s) acid(obtained from hydrolysis of the commercially available 3-Amino-4- methanesulfonyl- thiophene-2-carboxylic acid methyl ester)  63(IV) 491 127–129 (DMSO-D6) δ 1.42–1.96(8H, m), 2.26(3H, s), 2.32–2.41(2H, m), Example 2 step c (M+H) 2.53–2.59(2H, m), 2.67–3.11(4H, m), 3.24(3H, s), 4.28–4.35(2H, m), 6.77–6.81(1H, m), 6.95(1H, d), 7.26(1H, dd), 7.50(1H, ddd), 7.70(1H, d), 7.76–7.82(1H, m), 7.98(1H, ddd)  79(IV) 497 168–169 (DMSO-D6) δ 1.41–1.49(2H, m), 1.53–1.60(2H, m), 1.80(2H, d), Example 2 step c (M+H) 1.92(2H, dz), 2.27(3H, s), 2.38(2H, t), 2.54–2.62(2H, m), 2.77(2H, t), 2.93–3.12(2H, m), 3.40(3H, s), 4.33(2H, dt), 6.80(1H, dd), 6.95 (1H, d), 7.26(1H, d), 7.49(1H, d), 7.77(1H, d) 423(I) (M+H) 181–183 (DMSO-D⁶) δ 1.44–1.63(6H, m), 1.91–1.98(3H, m), 2.36–2.39 Example 2 step c 499 (2H, m), 2.53–2.62(4H, m), 2.76–2.90(2H, m), 3.03–3.11(1H, m), 3.34–3.42(1H, m), 4.40–4.45(1H, m), 4.56–4.64(1H, m), 6.96–6.99 (1H, m), 7.24(1H, s), 7.48–7.51(1H, m), 7.61–7.65(1H, m), 8.39–8.47(2H, m), 9.06–9.08(1H, m) 578(I) (M+H) 145–147 (DMSO-D⁶) δ 1.33–1.45(2H, m), 1.53–1.64(2H, m), 1.76–1.94 Example 2 step c 473 (4H, m), 2.36–2.44(2H, m), 2.55–2.64(1H, m), 2.70–2.80(3H, m), 3.03–3.15(1H, m), 4.35–4.44(1H, m), 4.51–4.61(1H, m), 5.08–5.20 (1H, m), 6.93–7.00(2H, m), 7.25–7.34(2H, m), 7.45–7.50 (1H, m), 7.57–7.63(1H, m), 8.33(1H, s), 8.50–8.62(1H, m) 580(I) (M+H) >200 (DMSO-D⁶) δ 1.43–1.65(4H, m), 1.85–1.96(3H, m), 2.32–2.41 Example 2 step c 500 (2H, m), 2.54–2.62(2H, m), 2.73–3.14(4H, m), 3.40–3.47(1H, m), 4.37–4.45(1H, m), 4.53–4.62(1H, m), 6.45(1H, d), 6.93–7.00(1H, m), 7.17–7.26(2H, m), 7.33–7.59(4H, m), 11.99(1H, s) 419(I) (M+H) >200 (DMSO-D⁶) δ 1.25–1.68(5H, m), 1.72–1.81(2H, m), 1.88–1.95 Example 2 step c 464 (2H, m), 2.22(3H, s), 2.31–2.40(2H, m), 2.60–2.78(3H, m), 2.92–3.00 (1H, m), 3.44–3.52(1H, m), 4.36–4.49(2H, m), 5.92–6.11(1H, m), 6.91–7.06(1H, m), 7.25(1H, s), 7.30–7.41(1H, m), 7.44–7.54 (1H, m), 11.86(1H, s) 550(I) (M+H) 80–85 (DMSO-D⁶) δ 1.40–1.65(5H, m), 1.83–1.96(3H, m), 2.31–2.43 Example 2 step c 484 (2H, m), 2.50–2.56(1H, m), 2.69–2.92(4H, m), 3.08–3.17(1H, m), 4.36–4.42(1H, m), 4.65–4.73(1H, m), 6.94–7.00(1H, m), 7.19–7.25 (1H, m), 7.45–7.50(1H, m), 7.58–7.71(3H, m), 8.00–8.05 (1H, m), 8.39–8.46(1H, m), 8.91–8.96(1H, m) 426(I) (M+H) 158–159 (DMSO-D6) δ 1.36–1.45(2H, m), 1.53–1.61(2H, m), 1.72–1.79 Example 2 step c 464 (2H, m), 1.88–1.96(2H, m), 2.35–2.43(2H, m), 2.52–2.57(1H, m), 2.72–2.79(2H, m), 2.85–2.94(2H, m), 3.32–3.38(1H, m), 3.49 (3H, s), 3.99–4.12(1H, m), 4.34–4.51(1H, m), 6.36(1H, d), 6.90–7.06 (1H, m), 7.21–7.29(1H, m), 7.42–7.54(2H, m), 7.91–8.03(1H, m) 416(I) (M+H) 133–135 (DMSO-D6) δ 1.38–1.45(2H, m), 1.53–1.60(2H, m), 1.66–1.84 Example 2 step c 448 (2H, m), 1.88–1.95(2H, m), 2.34–2.41(2H, m), 2.51–2.58(1H, m), 2.73–2.78(3H, m), 3.01–3.10(1H, m), 3.29–3.36(3H, m), 3.53–3.63 (1H, m), 4.38–4.53(2H, m), 6.94–7.01(1H, m), 7.21–7.28 (1H, m), 7.29–7.35(1H, m), 7.47–7.52(1H, m), 7.68–7.75(1H, m), 8.42–8.50(1H, m) 575(I) (M+H) 140–142 Example 2 step c 645 534(I) (M+H) 189–190 Example 2 step c 543 294(IV) (M+H) foam (CDCl₃) δ 1.32–1.45(1H, m), 1.56–1.71(2H, m), 1.79–2.01(5H, Example 2 step c 529 m), 2.46–2.61(3H, m), 2.79–2.87(3H, m), 2.92–3.16(4H, m), 3.36–3.42 (1H, m), 4.28–4.33(1H, m), 4.79(1H, t), 6.90(2H, dd), 7.12 (1H, dt), 7.49(1H, dd), 7.89(1H, ddd), 8.01(1H, dd)  67(IV) (M+H) 132–133 (CDCl₃) δ 1.38–1.65(2H, m), 1.73–2.04(6H, m), 2.40–2.67(3H, Example 2 step c 495 m), 2.72–2.89(3H, m), 2.99–3.08(1H, m), 3.23–3.28(3H, m), 3.33–3.53 (1H, m), 4.21–4.33(1H, m), 4.61–4.86(1H, m), 6.87–6.92(2H, m), 7.10–7.14(1H, m), 7.31–7.37(1H, m), 7.55–7.70(2H, m), 8.07 (1H, td)  83(IV) (M+H) foam (CDCl₃) δ 1.50–1.63(2H, m), 1.85–2.00(6H, m), 2.44–2.51(2H, Example 2 step c 501 m), 2.56–2.66(1H, m), 2.80–2.88(2H, m), 3.01(2H, s), 3.20(3H, s), 4.27–4.51(3H, m), 6.91(2H, dd), 7.13(1H, dt), 7.23(1H, d), 7.63 (1H, d) 295(IV) (M+H) (CDCl₃) δ 1.75–2.03(10H, m), 2.18–2.19(3H, m), 2.44–2.54(2H, Example 2 step c 491 m), 2.77–2.89(3H, m), 3.00–3.09(1H, m), 3.23–3.28(3H, m), 3.36–3.52 (1H, m), 4.63–4.85(1H, m), 6.70–6.75(1H, m), 7.05–7.11(2H, m), 7.31–7.37(1H, m), 7.56–7.68(2H, m), 8.05–8.10(1H, m) 568(I) (M+H) (DMSO-D6) δ 1.21–1.95(8H, m), 2.35–2.42(2H, m), 2.57–2.66 Example 2 step c 558 (1H, m), 2.72–2.77(2H, m), 3.08–3.17(1H, m), 4.08–4.13(1H, m), 4.29(2H, d), 4.40–4.46(3H, m), 6.96–7.00(1H, m), 7.25–7.26(1H, m), 7.48–7.51(1H, m), 7.58–7.62(1H, m), 8.01–8.07(2H, m), 8.40–8.43 (1H, m), 8.75–8.78(2H, m) 296(IV) (M+H) (CDCl₃) δ 1.58–1.68(4H, m), 1.85(2H, s), 2.00(2H, s), 2.19(3H, s), Example 2 step c 525 2.51–2.59(3H, m), 2.80–2.92(3H, m), 2.98–3.16(4H, m), 3.37–3.43 (1H, m), 4.33(1H, s), 4.76–4.85(1H, m), 6.72–6.74(1H, m), 7.06–7.12(2H, m), 7.45–7.53(1H, m), 7.88–7.91(1H, m), 8.00–8.02 (1H, m) 471(I) 472 δ 1.40(m, 2H), 1.57(m, 2H), 1.79(m, 2H), 1.90(m, 2H), 2.40(m, 2H), Example 2 step c (M+H) 2.58(m, 1H), 2.79(m, 2H), 2.87(m, 2H), 4.30(d, 2H), 4.43(m, 1H), 6.97(dd, 1H), 7.13(m, 2H), 7.25(d, 1H), 7.43(d, 1H), 7.49(d, 1H), 7.65(m, 2H) 475(I) 526 (DMSO-D6) δ 1.67–1.78(m, 2H), 1.95–2.09(m, 3H), 2.18–2.27(m, 2H), Example 2 step c (M+H) 2.44(d 3H), 2.77–2.88(m, 1H), 3.08–3.19(m, 3H), 3.33–3.52(m, 5H), 3.59–3.67(m, 1H), 4.60–4.68(m, 1H), 4.84(s, 1H), 7.05(ddd, 1H), 7.14–7.27(m, 1H), 7.37(dd, 1H), 7.55(t, 1H), 7.61 (q, 1H), 7.70–7.71(m, 2H), 7.78–7.80(m, 1H), 7.86–7.89(m, 1H), 569(I) 512 (DMSO-D6) δ 1.65–1.80(m, 2H), 1.99–2.09(m, 2H), 2.19–2.30(m, 3H), Example 2 step c (M+H) 2.77–2.90(m, 1H), 3.07–3.21(m, 3H), 3.30–3.37(m, 3H), 3.47–3.57(m, 2H), 3.59–3.71(m, 1H), 4.59–4.69(m, 1H), 4.82–4.86(m, 1H), 7.05(ddd, 1H), 7.37(dd, 1H), 7.49(s, 2H), 7.55(t, 1H), 7.64–7.69(m, 2H), 7.84–7.86(m, 1H), 7.92(td, 1H) 477(I) 507 (DMSO-D6) δ 1.64–1.78(m, 2H), 1.99–2.09(m, 2H), 2.17–2.29(m, 3H), Example 2 step c (M+H) 2.70–2.85(m, 1H), 3.04–3.19(m, 3H), 3.28–3.38(m, 3H), 3.31(s, 3H), 3.46–3.55(m, 2H), 3.66(t, 2H), 4.12(t, 2H), 4.56–4.68(m, 1H), 4.81–4.86(m, 1H), 6.94–6.97(m, 2H), 7.04(dd, 1H), 7.05 (ddd, 1H), 7.34–7.39(m, 2H), 7.55(t, 1H), 584(I) 592 (CDCl₃) δ 1.45(s, 9H), 1.48–1.67(m, 4H), 1.75–1.85(m, 2H), Example 2 step c (M+H) 1.90–2.03(m, 3H), 2.42–2.51(m, 2H), 2.56(m, 1H), 2.71–2.84(m, 3H), 2.91–3.06(m, 1H), 3.54(q, 2H), 3.75–3.88(m, 1H), 4.03(t, 2H), 4.27(septet, 1H), 4.68–4.82(m, 1H), 4.93–5.01(m, 1H), 6.75(dd, 1H), 6.90–7.00(m, 3H), 7.25–7.32(m, 3H) 325(I) 491 (DMSO-D6) δ 1.69–1.83(2H, m), 1.98–2.11(3H, m), 2.17–2.28 Example 2 step c using (M+H) (3H, m), 2.81–2.92(1H, m), 3.08–3.21(3H, m), 3.47–3.59(2H, m), acid prepared according 3.61–3.71(1H, m), 4.61–4.73(2H, m), 4.82–4.86(1H, m), 7.05 to Journal of (1H, ddd), 7.37(1H, dd), 7.56(1H, t), 7.77(1H, ddd), 8.51(1H, s), Heterocyclic 8.80(1H, d) chemistry, 1972, p1149 585(I) 507 (DMSO-D6) δ 1.70–1.78(m, 2H), 2.00–2.09(m, 2H), 2.18–2.26(m, 2H), Example 2 step c, (M+H) 3.05–3.17(m, 2H), 3.24–3.40(m, 2H), 3.97–4.06(m, 2H), using 3-tert- 4.44–4.52(m, 2H), 4.59–4.70(m, 2H), 4.73(s, 2H), 4.81–4.86(m, butoxycarbonyl- 1H), 4.91–4.93(m, 2H), 6.90–6.93(m, 1H), 6.96–7.04(m, 1H), methoxy-benzoic acid, 7.07–7.11(m, 1H), 7.17–7.20(m, 1H), 7.34–7.43(m, 2H), 7.52–7.55(m, 1H), followed by the addition of(1 M) HCl in ether to form final compound as hydrochloride salt. (HCl also cleaved tert-butyl ester to leave acid.) 586(I) 492 (DMSO-D6) δ 1.56–1.87(3H, m), 1.94–2.17(5H, m), 3.06–3.27(7H, Prepared by (M+H) m), 3.50–3.78(3H, m), 4.19(2H, t), 4.57–4.69(1H, m), 4.80–4.85(1H, deprotection of 584(I) m), 6.98–7.10(4H, m), 7.34–7.44(2H, m), 7.57(1H, dd) using trifluoroacetic acid in dichloromethane 588(I) 551   145 (CDCl₃) δ 0.09(2H, dd), 0.44(2H, dd), 0.83–0.89(1H, m), 1.67–1.78 Example 2 step c (M+H) (2H, m), 1.96–2.09(3H, m), 2.18–2.28(4H, m), 2.78–2.89(1H, m), 3.08–3.20(4H, m), 3.34(2H, s), 3.47–3.65(3H, m), 4.59–4.68 (1H, m), 4.84(1H, s), 7.05(1H, ddd), 7.36(1H, dd), 7.55(1H, t), 7.73–7.81 (2H, m), 7.90(1H, t), 8.00(1H, d)  71(IV) 497 (CDCl₃) δ 1.56(2H, qd), 1.79–1.99(8H, m), 2.19(3H, s), 2.45–2.52 Example 2 step c (M+H) (2H, m), 2.60(1H, tt), 2.76–2.83(2H, m), 2.91–3.11(2H, m), 3.21 (3H, s), 4.28–4.35(1H, m), 6.74(1H, d), 7.05–7.12(2H, m), 7.24 (1H, d), 7.63(1H, d) 245(IV) 486 120–126 (CDCl₃) δ 1.45–1.61(2H, m), 1.80–2.03(6H, m), 2.19(3H, s), 2.45–2.53 Example 2 step c using 2-Oxo-2,3- (M+H) (2H, m), 2.54–2.62(1H, m), 2.79–3.09(4H, m), 3.80–3.99(1H, dihydro-benzothiazole-6-carboxylic m), 4.28–4.34(1H, m), 4.62–4.81(1H, m), 6.73(1H, d), 7.05–7.12 acid prepared according to Chem. (3H, m), 7.30(1H, dd), 7.47(1H, d) Pharm. Bull. 1988, 36, p2253 297(IV) 526 115–117 (CDCl₃) δ 1.42–1.64(2H, m), 1.78–1.87(3H, m), 1.93–2.01(3H, Example 2 step c (M+H) m), 2.19(3H, s), 2.44–2.51(2H, m), 2.57(1H, tt), 2.75–2.88(3H, m), 3.01–3.14(1H, m), 3.64–3.73(1H, m), 4.27–4.33(1H, m), 4.65–4.74 (1H, m), 6.73(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.52(1H, dd), 7.58(1H, d), 8.11(1H, d) 298(IV) 480 120–126 (CDCl₃) δ 1.31–1.66(2H, m), 1.70–2.05(6H, m), 2.19(3H, s), 2.38–2.60 Example 2 step c (M+H) (3H, m), 2.73–2.83(2H, m), 2.85–3.11(2H, m), 3.71–3.86(1H, m), 4.26–4.35(1H, m), 4.76–4.92(1H, m), 6.73(1H, d), 7.07(1H, dd), 7.11(1H, s), 7.19–7.34(1H, m), 7.57(1H, t), 7.59–7.68(1H, m), 7.73(1H, t), 8.46(1H, d) 214(IV) 514    96 (CDCl₃) δ 1.42–1.62(2H, m), 1.74–2.02(6H, m), 2.19(3H, s), 2.44–2.61 Example 2 step c (M+H) (3H, m), 2.75–2.85(3H, m), 2.95–3.11(1H, m), 3.42(2H, s), 3.45(3H, s), 3.78–3.93(1H, m), 4.26–4.36(1H, m), 4.64–4.81(1H, m), 6.74(1H, d), 7.02–7.15(3H, m), 7.27(1H, s), 7.38(1H, d) 589(I) 540 (CDCl₃) δ 1.52–1.62(2H, m), 1.68(1H, d), 1.84(1H, d), 1.92(2H, d), Example 2 step c (M+H) 2.35–2.42(2H, m), 2.52–2.55(1H, m), 2.63(6H, s), 2.72–2.83(3H, m), 2.99–3.13(2H, m), 3.46–3.56(2H, m), 4.38–4.45(1H, m), 4.49 (1H, d), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 7.73–7.75(2H, m), 7.81–7.83(1H, m), 8.31(1H, s) 590(I) 556 (DMSO-D6) δ 1.43–1.62(4H, m), 1.66(1H, d), 1.85(1H, d), 1.89–1.97 Example 2 step c (M+H) (2H, m), 2.35–2.44(3H, m), 2.73–2.87(3H, m), 3.11(1H, t), 3.42(3H, s), 3.52(1H, d), 4.39–4.46(1H, m), 4.50(1H, d), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 8.36(1H, t), 8.54(1H, t), 8.67(1H, t) 591(I) 526 (DMSO-D6) δ 1.29–1.39(2H, m), 1.90(2H, d), 2.11–2.18(1H, m), Example 2 step c (M+H) 2.39(2H, t), 3.13(2H, t), 3.44–3.52(2H, m), 3.65–3.73(2H, m), 3.82–3.91(4H, m), 3.94–4.01(2H, m), 4.47–4.57(1H, m), 6.15 (1H, d), 6.88–6.93(1H, m), 6.95(1H, dd), 7.03(1H, d), 7.31(1H, t), 7.62–7.65(1H, m), 8.32–8.51(2H, m), 8.95(1H, t) 593(I) 536 (DMSO-D6) δ 1.42–1.63(4H, m), 1.66(1H, d), 1.84(1H, d), 1.89–1.97 Example 2 step c (M+H) (2H, m), 2.32–2.45(1H, m), 2.50–2.61(2H, m), 2.72–2.87(3H, m), 3.08(1H, t), 3.37(3H, s), 3.48(1H, d), 4.37–4.46(1H, m), 4.46–4.55 (1H, m), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 8.21(1H, t), 8.30(1H, t), 8.48(1H, t) 594(I) 550 (DMSO-D6) δ 1.38–1.52(2H, m), 1.53–1.64(2H, m), 1.84(2H, d), Example 2 step C (M+H) 1.88–1.98(2H, m), 2.37–2.45(4H, m), 2.58–2.68(1H, m), 2.74–2.82 (3H, m), 3.17(3H, s), 4.37–4.50(2H, m), 6.99(1H, dd), 7.00–7.02 (1H, m), 7.26(1H, d), 7.49(1H, d), 7.61(1H, d), 7.70(1H, dd), 8.23(1H, d) 299(IV) 525 (DMSO-D6) δ 1.38–1.5(2H, m), 1.60–1.70(2H, m), 1.81–2.00 Example 12 (M+H) (2H, m), 2.40(3H, s), 2.41–3.31(9H, m), 3.35(3H, s), 3.41–3.58 (1H, m), 4.4–4.55(2H, m), 7.09(1H, d), 7.34(1H, d), 7.71(2H, m), 7.90(1H, s), 8.0(1H, m) 300(IV) 489 (DMSO-D6) δ 1.10(3H, t), 1.35–1.50(2H, m), 1.58–1.70(2H, m), Example 12 (M+H) 1.81–1.97(2H, m), 2.25–3.20(11H, m), 3.32(3H, s), 3.4–3.6(1H, m), 4.25–4.6(2H, m), 6.85–7.00(3H, m), 7.63–7.78(2H, m), 7.90 (1H, s), 7.98–8.02(1H, m) 143(IV) 465 (CDCl₃) δ 1.63–1.74(2H, m), 1.78–1.88(3H, m), 1.92–2.04(3H, Example 2 step c (M+H) m), 2.19(3H, s), 2.43–2.55(2H, m), 2.64(1H, tt), 2.76–2.94(3H, m), 3.13–3.27(1H, m), 4.25–4.35(2H, m), 4.82–4.90(1H, m), 6.74 (1H, d), 7.07(1H, dd), 7.11(1H, d), 7.56(1H, dd), 7.85(1H, d), 8.25 (1H, dd), 8.32(1H, d), 9.19(1H, dd) 301(IV) 530 (CDCl₃) δ 1.57–1.71(2H, m), 1.80–1.91(3H, m), 1.95–2.06(3H, Example 2 step c (M+H) m), 2.20(3H, s), 2.47–2.55(2H, m), 2.61–2.72(1H, m), 2.79–2.86 (2H, m), 2.91–3.35(2H, m), 3.08(3H, s), 4.28–4.37(1H, m), 4.69–4.80 (2H, m), 6.74(1H, d), 6.90(1H, d), 7.07(1H, dd), 7.12(1H, d), 7.57(1H, d), 7.79(1H, dd), 8.32(1H, d) 572(I) 500 (CDCl₃) δ 1.37–1.66(2H, m), 1.73–1.88(3H, m), 1.93–2.05(3H, Example 2 step c (M+H) m), 2.41–2.51(2H, m), 2.52–2.63(1H, m), 2.75–2.86(2H, m), 2.86–3.09 (2H, m), 3.71–3.90(1H, m), 4.23–4.32(1H, m), 4.77–4.93(1H, m), 6.75(1H, dd), 6.99(1H, d), 7.27–7.32(3H, m), 7.54–7.67(1H, m), 7.57(1H, t), 7.74(1H, t), 8.46(1H, d) 120(IV) 480 (CDCl₃) δ 1.46–1.66(2H, m), 1.79–2.01(6H, m), 2.19(3H, s), 2.45–2.52 Example 2 step c using acid available (M+H) (2H, m), 2.59(1H, tt), 2.75–2.84(2H, m), 2.92–3.20(2H, m), from Bionet Research Ltd., Highfield 3.74–4.00(1H, m), 4.27–4.35(1H, m), 4.55–4.90(1H, m), 6.49 Industrial Estate, Camelford, (1H, dd), 6.74(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.76(1H, d), 7.88 Cornwall, PL32 9QZ, United (1H, dd), 8.03(1H, d), 8.48(1H, d), 8.57(1H, d) Kingdom 145(IV) 538 (CDCl₃) δ 1.35–1.73(2H, m), 1.77–1.89(3H, m), 1.92–2.06(3H, Example 2 step c using acid available (M+H) m), 2.19(3H, s), 2.43–2.64(3H, m), 2.74–2.83(2H, m), 2.83–2.94 from Peakdale Inc. (1H, m), 3.00–3.12(1H, m), 3.38–3.54(1H, m), 4.26–4.35(1H, m), 109 East Scotland Drive 4.76–4.92(1H, m), 6.73(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.70 Bear, DE, 19701–1756 (1H, d), 7.98(1H, dd), 8.19(1H, d) USA 240(IV) 465 (CDCl₃) δ 1.62–1.74(2H, m), 1.77–1.86(3H, m), 1.93–2.03(3H, Example 2 step c (M+H) m), 2.33(3H, s), 2.41–2.54(2H, m), 2.65(1H, tt), 2.78–2.86(1H, m), 2.89(2H, td), 3.21(1H, td), 4.21–4.35(2H, m), 4.81–4.90(1H, m), 6.67(1H, dd), 6.78(1H, d), 7.20(1H, d), 7.57(1H, dd), 7.85(1H, d), 8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd) 267(IV) 453 (CDCl₃) δ 1.62(2H, qd), 1.79–2.01(6H, m), 2.19(3H, s), 2.43–2.52 Example 2 step c (M+H) (2H, m), 2.64(1H, tt), 2.74–2.85(2H, m), 3.12–3.22(1H, m), 4.26–4.32 (1H, m), 4.77–4.86(1H, m), 5.24–5.33(1H, m), 6.74(1H, d), 6.84(1H, td), 7.07(1H, dd), 7.11(1H, d), 7.21(1H, dd), 7.23(1H, dd), 7.60(1H, dd), 8.06(1H, d), 8.13(1H, dt) 199(IV) 470 (CDCl₃) δ 1.57–1.67(2H, m), 1.81–1.88(2H, m), 1.93–2.01(4H, Example 2 step c (M+H) m), 2.20(3H, s), 2.50(2H, td), 2.65(1H, tt), 2.82(2H, td), 2.96–3.20 (2H, m), 4.28–4.35(1H, m), 4.74(2H, d), 6.73–6.75(2H, m), 7.01–7.12 (3H, m), 7.28(1H, d), 7.35(1H, dd), 9.35(1H, s) 181(IV) 538 (CDCl₃) δ 1.50–1.65(2H, m), 1.70–1.83(3H, m), 1.93–2.04(3H, Example 2 step c (M+H) m), 2.32(3H, s), 2.40–2.50(2H, m), 2.52–2.62(1H, m), 2.76–2.92 (3H, m), 3.01–3.10(1H, m), 3.38–3.52(1H, m), 4.22–4.30(1H, m), 4.77–4.90(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d), 7.70 (1H, d), 7.98(1H, dd), 8.19(1H, d) 216(IV) 526 (CDCl₃) δ 1.47–1.66(2H, m), 1.79–1.88(3H, m), 1.95–2.04(3H, Example 2 step c (M+H) m), 2.32(3H, s), 2.53–2.61(2H, m), 2.70(1H, tt), 2.76–2.89(3H, m), 2.99–3.13(1H, m), 3.63–3.74(1H, m), 4.27–4.33(1H, m), 4.63–4.77 (1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d), 7.50(1H, dd), 7.56(1H, d), 8.09(1H, d) 266(IV) 480 (CDCl₃) δ 1.37–1.67(2H, m), 1.76–1.85(3H, m), 1.93–2.01(3H, Example 2 step c (M+H) m), 2.32(3H, s), 2.41–2.48(2H, m), 2.50–2.60(1H, m), 2.77–2.85 (2H, m), 2.86–3.10(2H, m), 3.73–3.85(1H, m), 4.23–4.29(1H, m), 4.77–4.92(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d), 7.21–7.31 (1H, m), 7.54–7.68(1H, m), 7.56(2H, t), 7.73(1H, t), 8.46(1H, d) 540(I) 485 (CDCl₃) δ 1.69–1.84(4H, m), 1.95–2.02(4H, m), 2.43–2.53(2H, Example 2 step c (M+H) m), 2.65(1H, tt), 2.79–2.93(3H, m), 3.18–3.25(1H, m), 4.23–4.35 (2H, m), 4.82–4.90(1H, m), 6.75(1H, dd), 7.00(1H, d), 7.31(1H, d), 7.57(1H, dd), 7.86(1H, d), 8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd) 204(IV) 470 (CDCl₃) δ 1.57–1.67(2H, m), 1.77–1.85(2H, m), 1.94–2.02(4H, Example 2 step c (M+H) m), 2.33(3H, s), 2.45–2.52(2H, m), 2.61–2.69(1H, m), 2.81–2.86 (2H, m), 2.97–3.18(2H, m), 4.24–4.30(1H, m), 4.74(2H, d), 6.68 (1H, dd), 6.73(1H, d), 6.78(1H, d), 7.04(1H, td), 7.20(1H, d), 7.28 (1H, d), 7.35(1H, dd), 9.34(1H, s). 104(IV) 480 (CDCl₃) δ 1.49–1.63(2H, m), 1.76–2.00(6H, m), 2.33(3H, s), 2.43–2.49 Example 2 step c (M+H) (2H, m), 2.59(1H, tt), 2.79–2.85(3H, m), 3.00–3.18(1H, m), 3.81–3.96(1H, m), 4.24–4.29(1H, m), 4.67–4.83(1H, m), 6.49 (1H, dd), 6.67(1H, dd), 6.78(1H, d), 7.20(1H, d), 7.76(1H, d), 7.88 (1H, dd), 8.03(1H, d), 8.48(1H, d), 8.57(1H, d) 243(IV) 486 (DMSO-D6/CDCl₃) δ 1.43–1.59(2H, m), 1.73–1.98(6H, m), 2.32 Example 2 step c (M+H) (3H, s), 2.43–2.48(2H, m), 2.79–2.87(2H, m), 2.91–3.40(5H, m), 4.23–4.30(1H, m), 6.68(1H, dd), 6.78(1H, d), 7.14(1H, d), 7.19 (1H, d), 7.26(1H, dd), 7.43(1H, d), 7.51(1H, s). 191(IV) 514 (CDCl₃) δ 1.46–1.59(2H, m), 1.76–2.00(6H, m), 2.32(3H, s), 2.44–2.48 Example 2 step c (M+H) (2H, m), 2.54–2.59(1H, m), 2.78–2.85(3H, m), 3.42(3H, s), 3.45(3H, s), 3.79–3.92(1H, m), 4.23–4.30(1H, m), 4.67–4.79(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.02(1H, d), 7.15(1H, s), 7.20(1H, d), 7.37(1H, d) 519(I) 490 (CDCl₃) δ 1.61(2H, qd), 1.77–1.85(2H, m), 1.94–2.02(4H, m), 2.38–2.51 Example 2 step c (M+H) (2H, m), 2.65(1H, tt), 2.80–2.85(2H, m), 2.95–3.14(2H, m), 4.25–4.30(1H, m), 4.73–4.77(2H, m), 6.73(1H, d), 6.75(1H, dd), 7.00(1H, d), 7.03(1H, td), 7.27(1H, dd), 7.31(1H, d), 7.35(1H, dd), 9.49(1H, s) 494(I) 558 (CDCl₃) δ 1.48–1.71(2H, m), 1.74–1.83(3H, m), 1.93–2.03(3H, Example 2 step c (M+H) m), 2.42–2.50(2H, m), 2.55–2.62(1H, m), 2.76–2.93(3H, m), 3.01–3.10 (1H, m), 3.40–3.50(1H, m), 4.22–4.31(1H, m), 4.77–4.90(1H, m), 6.75(1H, dd), 6.98(1H, d), 7.30(1H, d), 7.67(1H, d), 7.98(1H, dd), 8.19(1H, d) 238(IV) 511 172–173 (CDCl₃) δ 1.53–1.63(2H, m), 1.82–1.89(3H, m), 2.00–2.05(3H, Example 21 (M+H) m), 2.05–2.61(3H, m), 2.80–2.84(3H, m), 2.98–3.09(1H, m), 3.03 (3H, s), 3.77(1H, br s), 4.41–4.45(1H, m), 4.70(1H, br s), 6.99(2H, d), 7.21–7.26(1H, m), 7.44–7.54(2H, m), 7.86(2H, d) 496(I) 500 (DMSO-D6) δ 1.46(2H, qd), 1.54–1.61(2H, m), 1.65–1.88(3H, m), Example 2 step c (M+H) 1.89–1.97(2H, m), 2.37–2.42(2H, m), 2.54–2.61(1H, m), 2.73–2.83 (2H, m), 3.04–3.17(1H, m), 3.61–3.72(1H, m), 4.39–4.56(2H, m), 6.62(1H, dd), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 7.87(1H, dd), 7.97(1H, dd), 8.04(1H, dd), 8.52(1H, dd), 8.65(1H, dd) 483(I) 506 (DMSO-D6) δ 1.41(2H, qd), 1.53–1.62(2H, m), 1.68–1.82(2H, m), Example 2 step c (M+H) 1.89–1.96(2H, m), 2.36–2.43(3H, m), 2.53–2.59(3H, m), 2.74–2.80 (3H, m), 4.39–4.45(1H, m), 6.97(1H, dd), 7.13(1H, d), 7.25 (1H, d), 7.30(1H, dd), 7.49(1H, d), 7.66(1H, d) 302(IV) 498 (CDCl₃) δ 1.40–1.74(2H, m), 1.79–2.02(6H, m), 2.20(3H, s), 2.42–2.61 Example 2 step c (M+H) (3H, m), 2.67(1H, td), 2.74–2.84(2H, m), 3.16(1H, t), 3.91–4.00 (1H, m), 4.26–4.36(1H, m), 4.58–4.78(5H, m), 6.74(1H, d), 6.76–6.79(1H, m), 6.98–7.02(3H, m), 7.07(1H, dd), 7.12(1H, d) 303(IV) 498 (CDCl₃) δ 1.42–1.61(2H, m), 1.77–1.90(3H, m), 1.93–2.03(3H, Example 2 step c (M+H) m), 2.33(3H, s), 2.41–2.49(2H, m), 2.57(1H, tt), 2.67(1H, t), 2.77–2.84 (2H, m), 3.16(1H, t), 3.95(1H, d), 4.24–4.29(1H, m), 4.59–4.77 (5H, m), 6.68(1H, dd), 6.75–6.79(2H, m), 6.97–7.00(3H, m), 7.21(1H, d) 596(I) 518 (CDCl₃) δ 1.43–1.64(2H, m), 1.77–1.89(3H, m), 1.94–2.01(3H, Example 2 step c (M+H) m), 2.41–2.50(2H, m), 2.57(1H, tt), 2.68(1H, t), 2.76–2.83(2H, m), 3.16(1H, t), 3.94–3.97(1H, m), 4.24–4.30(1H, m), 4.58–4.63(1H, m), 4.68(2H, s), 4.76(2H, d), 6.76–6.78(2H, m), 6.98–7.00(3H, m), 7.26(1H, s), 7.31(1H, d) 467(I) 534 (DMSO-D6) δ 1.35–1.50(2H, m), 1.52–1.65(3H, m), 1.68–1.84 Example 2 step c (M+H) (2H, m), 1.88–1.98(2H, m), 2.35–2.44(2H, m), 2.54–2.61(1H, m), 2.73–2.82(3H, m), 3.37(3H, s), 3.57(2H, s), 3.60–3.71(1H, m), 4.38–4.56(2H, m), 6.98(1H, dd), 7.07(1H, dd), 7.24(1H, d), 7.26 (1H, d), 7.47(1H, d), 7.50(1H, d) 269(IV) 453 (CDCl₃) δ 1.55–1.68(4H, m), 1.75–2.01(4H, m), 2.33(3H, s), 2.41–2.51 Example 2 step c (M+H) (2H, m), 2.64(1H, tt), 2.78–2.87(3H, m), 3.12–3.24(1H, m), 4.21–4.29(1H, m), 4.76–4.88(1H, m), 5.23–5.34(1H, m), 6.67 (1H, dd), 6.78(1H, d), 6.84(1H, t), 7.19–7.26(2H, m), 7.60(1H, d), 8.06(1H, s), 8.13(1H, dd) 597(I) 546 (CDCl₃) δ 1.39–1.66(2H, m), 1.73–1.86(4H, m), 1.92–2.03(2H, Example 2 step c (M+H) m), 2.41–2.50(2H, m), 2.53–2.63(1H, m), 2.76–2.88(2H, m), 2.98–3.12 (1H, m), 3.62–3.77(1H, m), 4.24–4.29(1H, m), 4.62–4.78(1H, m), 6.75(1H, dd), 6.99(1H, d), 7.31(2H, d), 7.53(1H, dd), 7.57(1H, t), 8.12(1H, d) 598(I) 474 (CDCl₃) δ 1.58–1.75(2H, m), 1.80–1.88(2H, m), 1.91–2.05(4H, Example 2 step c (M+H) m), 2.53–2.61(2H, m), 2.71–2.90(4H, m), 3.18–3.22(1H, m), 4.27–4.33 (1H, m), 4.84(1H, d), 5.55(1H, d), 6.75(1H, dd), 6.95(1H, dd), 7.00(1H, d), 7.31(1H, d), 8.09(1H, s), 8.46(1H, dd), 8.62(1H, dd) 579(I) 491 (CDCl₃) δ 1.61(1H, qd), 1.75–2.02(7H, m), 2.42–2.51(2H, m), 2.59–2.67 Example 2 step c (M+H) (1H, m), 2.75–2.86(3H, m), 3.12–3.21(1H, m), 4.23–4.29 (1H, m), 4.76–4.85(1H, m), 5.23–5.32(1H, m), 6.75(1H, dd), 6.99 (1H, d), 7.16(1H, ddd), 7.30(1H, d), 7.58(1H, dd), 8.07(2H, s) 599(I) 487 (CDCl₃) δ 1.58–1.67(1H, m), 1.75–2.02(7H, m), 2.43–2.51(3H, Example 2 step c (M+H) m), 2.59–2.68(1H, m), 2.61(3H, s), 2.76–2.85(3H, m), 3.12–3.23 (1H, m), 4.23–4.28(1H, m), 4.78–4.87(1H, m), 5.30–5.38(1H, m), 6.67(1H, d), 6.75(1H, dd), 7.20(1H, dd), 7.30(1H, d), 7.51(1H, d), 8.01(1H, s) 600(I) 507 (CDCl₃) δ 1.61(1H, qd), 1.70–2.04(7H, m), 2.41–2.53(2H, m), 2.63 Example 2 step c (M+H) (1H, t), 2.73–2.88(3H, m), 3.09–3.23(1H, m), 4.21–4.31(1H, m), 4.74–4.86(1H, m), 5.20–5.30(1H, m), 6.75(1H, dd), 6.99(1H, d), 7.19(1H, d), 7.30(1H, d), 7.55(1H, d), 8.04(1H, s), 8.19(1H, s) 304(IV) 505 (CDCl₃) δ 1.57–1.68(2H, m), 1.82–2.01(6H, m), 2.46–2.54(2H, Example 2 step c (M+H) m), 2.46(3H, s), 2.59–2.69(1H, m), 2.73–2.90(3H, m), 3.10–3.23 (1H, m), 4.32–4.39(1H, m), 4.76–4.85(1H, m), 5.22–5.32(1H, m), 6.75(1H, d), 7.14–7.27(2H, m), 7.58(1H, dd), 8.07(2H, s) 601(I) 487 (CDCl₃) δ 1.55–1.65(1H, m), 1.75–2.01(7H, m), 2.40(3H, s), 2.44–2.50 Example 2 step c (M+H) (2H, m), 2.63(1H, qt), 2.73–2.86(3H, m), 3.10–3.22(1H, m), 4.22–4.28(1H, m), 4.75–4.86(1H, m), 5.22–5.34(1H, m), 6.66 (1H, dd), 6.75(1H, dd), 6.99(1H, d), 7.30(1H, d), 7.34(1H, s), 7.97 (1H, s), 7.99(1H, d) 343(I) 566 (CDCl₃) δ 1.39–1.65(1H, m), 1.77–1.89(4H, m), 1.94–2.03(3H, Example 2 step c (M+H) m), 2.43–2.50(2H, m), 2.54–2.62(1H, m), 2.77–2.90(3H, m), 3.03–3.31 (1H, m), 3.53(3H, s), 3.65–3.74(1H, m), 4.26–4.31(1H, m), 4.26(2H, s), 4.69–4.79(1H, m), 6.75(1H, dd), 6.99(1H, d), 7.26–7.35 (3H, m), 8.00(1H, d) 603(I) 526 (CDCl₃) δ 1.49–1.58(2H, m), 1.76–1.84(3H, m), 1.90–2.01(4H, Example 2 step c (M+H) m), 2.44–2.48(2H, m), 2.53–2.59(1H, m), 2.78–2.82(2H, m), 2.78–3.00 (5H, m), 3.15–3.19(1H, m), 4.24–4.29(1H, m), 4.96(2H, s), 6.74–6.80(2H, m), 6.99(1H, d), 7.31(1H, d), 7.66–7.70(2H, m) 534(I) 543 (CDCl₃) δ 1.49(3H, t), 1.57–2.00(6H, m), 2.43–2.52(2H, m), 2.56–2.62 Example 2 step c (M+H) (3H, m), 2.67(3H, s), 2.78–2.84(3H, m), 3.10–3.19(1H, m), 3.74(1H, d), 4.25(1H, dquintet), 4.42–4.49(2H, m), 4.76(1H, d), 6.75(1H, dd), 6.99(1H, d), 7.23(1H, d), 7.30(1H, d), 8.09(1H, s), 8.60(1H, d)  5(II) 474 Example 2 step c (M+H)  6(II) 468 (DMSO–D6) δ 1.39–1.45(1H, m), 1.54–1.93(6H, m), 2.32–2.39 Example 2 step c (M+H) (2H, m), 2.49–2.53(2H, m), 2.72–3.02(4H, m), 3.29–3.32(2H, m), 4.31–4.34(1H, m), 6.75–6.79(1H, m), 7.08(1H, ddd), 7.30(2H, dt), 7.49–7.56(2H, m), 7.76(1H, t), 8.24(1H, dd)  7(II) 453 (DMSO-D6) δ 1.45–1.69(5H, m), 1.84–1.99(3H, m), 2.40(2H, t), Example 2 step c (M+H) 2.59–2.66(1H, m), 2.73–2.92(3H, m), 3.03–3.14(1H, m), 3.69–3.76 (1H, m), 4.31–4.37(1H, m), 4.55–4.61(1H, m), 6.78(1H, dd), 7.09(1H, ddd), 7.31(1H, dt), 7.69–7.78(2H, m), 8.49–8.65(2H, m), 9.15(1H, dd)  8(II) 441 (DMSO–D6) δ 1.34–1.45(2H, m), 1.52–1.61(2H, m), 1.76–1.86 Example 2 step c (M+H) (2H, m), 1.87–1.96(2H, m), 2.33–2.44(2H, m), 2.56–2.63(1H, m), 2.72–2.81(3H, m), 3.05–3.14(1H, m), 4.29–4.38(1H, m), 4.51–4.61 (1H, m), 5.09–5.19(1H, m), 6.73–6.79(1H, m), 6.94–6.99 (1H, m), 7.04–7.12(1H, m), 7.28–7.34(2H, m), 7.61(1H, dd), 8.30 (1H, s), 8.56(1H, dt) 305(IV) 514 (DMSO-D6) δ 1.42–1.51(2H, m), 1.60–1.93(6H, m), 2.41–2.47 Example 2 step c (M+H) (2H, m), 2.41(3H, s), 2.54–2.60(1H, m), 2.72–2.80(2H, m), 3.05–3.15 (1H, m), 3.29–3.35(1H, m), 3.60–3.71(1H, m), 4.44–4.54(2H, m), 6.59–6.64(1H, m), 7.07–7.13(1H, m), 7.31–7.38(1H, m), 7.86–7.89 (1H, m), 7.95–7.99(1H, m), 8.01–8.07(1H, m), 8.50–8.54(1H, m), 8.63–8.67(1H, m) 306(IV) 531 (DMSO-D6) δ 1.39–1.95(8H, m), 2.40(3H, s), 2.42–2.47(2H, m), Example 2 step c (M+H) 2.55–2.63(2H, m), 2.72–2.81(2H, m), 2.94–3.09(2H, m), 3.42(3H, s), 4.14–4.32(1H, m), 4.46–4.54(1H, m), 7.10(1H, d), 7.36(1H, d), 7.49(1H, d), 7.78(1H, d) 307(IV) 525 (DMSO-D6) δ 1.39–1.95(9H, m), 2.42(3H, s), 2.44–2.48(1H, m), Example 2 step c (M+H) 2.55–2.61(1H, m), 2.70–2.83(2H, m), 2.99–3.10(1H, m), 3.29 (3H, s), 3.41–3.52(2H, m), 4.46–4.58(2H, m), 7.11(1H, d), 7.36 (1H, d), 7.66(2H, dd), 7.99(2H, dd) 308(IV) 512 (DMSO-D6) δ 1.60–4.25(18H, m), 4.55–4.80(1H, m), 5.22–5.45(1H, Prepared in a similar manner to (M+H) m), 7.05(1H, t), 7.75–7.82(2H, m), 7.85(1H, s), 8.00–8.18(2H, m), Example 15 and isolated as the 8.60(1H, s), 9.63(1H, br s) trifluoroacetate salt  1(V) 509 87–88 (DMSO-D⁶) δ 1.11–1.18(2H, m), 1.36–1.53(4H, m), 1.63–1.78 Example 2 step c (M+H) (2H, m), 2.07(2H, t), 2.48–2.52(2H, m), 2.81–2.84(4H, m), 3.01–3.04 (2H, m), 3.27–3.27(3H, m), 3.49–3.50(1H, m), 4.44–4.53(1H, m), 7.15–7.18(1H, m), 7.44–7.45(1H, m), 7.50–7.53(1H, m), 7.69–7.76 (2H, m), 7.90(1H, t), 7.98–8.02(1H, m)  2(V) 510 (CDCl₃) δ 1.38–1.48(3H, m), 1.59(1H, br s), 1.81–2.07(4H, m), Example 12 (M+H) 2.34(2H, t), 2.55–2.60(1H, m), 2.84–2.92(3H, m), 3.07 4H, s), 3.21 (1H, br s), 3.60(1H, d), 3.68(1H, br s), 4.74(1H, br s), 6.41(1H, dd), 6.64(1H, d), 7.16(1H, d), 7.62–7.70(2H, m), 7.97–8.02(2H, m)  3(V) 523 (DMSO-D6) δ 1.42–1.56(4H, m), 1.64–1.86(4H, m), 2.33(2H, t), Prepared in a similar maner to (M+H) 2.54–2.61(1H, m), 2.76–2.85(1H, m), 2.87–2.93(2H, m), 3.04–3.12 Example 12 using(3,4-Dichloro- (1H, m), 3.28(3H, s), 3.36–3.44(1H, m), 3.48–3.57(1H, m), phenyl)-piperidin-4-yl-methanone 4.47–4.55(1H, m), 7.70–7.77(2H, m), 7.80(1H, d), 7.91–7.95(2H, hydrochloride(free base was made m), 8.00(1H, dt), 8.14–8.16(1H, m) insitu using triethylamine 310(IV) 478 169–170 (DMSO-D6) δ 1.29–1.40(2H, m), 1.53–1.62(2H, m), 1.71–1.77 Example 26 using 4- (M+H) (2H, m), 1.89–1.96(2H, m), 2.35–2.42(2H, m), 2.45–2.49(1H, m), Methoxyphenylisocyanate 2.68–2.79(4H, m), 3.70(3H, s), 4.10–4.17(2H, m), 4.38–4.45(1H, m), 6.78–6.82(2H, m), 6.98(1H, dd), 7.25(1H, d), 7.30–7.34(2H, m), 7.49(1H, d), 8.30(1H, s) 311(IV) 466   217 (DMSO-D6) δ 1.29–1.40(2H, m), 1.53–1.62(2H, m), 1.72–1.78 Example 26 using 4- (M+H) (2H, m), 1.89–1.96(2H, m), 2.36–2.42(2H, m), 2.44–2.49(1H, m), Fluorophenylisocyanate 2.71–2.79(4H, m), 4.11–4.17(2H, m), 4.38–4.45(1H, m), 6.98 (1H, dd), 7.05(2H, t), 7.25(1H, d), 7.45(2H, tt), 7.49(1H, d), 8.50(1H, s) 312(IV) 494 170–172 (DMSO-D6) δ 1.29–1.40(2H, m), 1.52–1.62(2H, m), 1.72–1.78 Example 26 using 3- (M+H) (2H, m), 1.89–1.96(2H, m), 2.36–2.42(2H, m), 2.43(3H, s), 2.44–2.48 (Methylthio)phenylisocyanate (1H, m), 2.71–2.79(4H, m), 4.15(2H, d), 4.38–4.45(1H, m), 6.81(1H, d), 6.98(1H, dd), 7.15(1H, t), 7.24–7.27(2H, m), 7.43(1H, t), 7.49(1H, d), 8.48(1H, s) 313(IV) 462 178–179 (DMSO-D6) δ 1.22–1.34(2H, m), 1.52–1.61(2H, m), 1.65–1.72 Example 26 using Benzylisocyanate (M+H) (2H, m), 1.88–1.95(2H, m), 2.33–2.46(3H, m), 2.61–2.76(4H, m), 3.99–4.05(2H, m), 4.22(2H, d), 4.37–4.44(1H, m), 6.97(1H, dd), 7.04(1H, t), 7.18–7.31(6H, m), 7.49(1H, d) 314(IV) 492 166–167 (DMSO-D6) δ 1.21–1.32(2H, m), 1.51–1.61(2H, m), 1.64–1.71 Example 26 using 4- (M+H) (2H, m), 1.88–1.95(2H, m), 2.32–2.46(3H, m), 2.59–2.67(2H, m), Methoxybenzylisocyanate 2.69–2.76(2H, m), 3.71(3H, s), 4.01(2H, d), 4.14(2H, d), 4.37–4.44 (1H, m), 6.83–6.87(2H, m), 6.94–6.99(2H, m), 7.14–7.18(2H, m), 7.25(1H, d), 7.49(1H, d) 315(IV) 480 209–210 (DMSO-D6) δ 1.21–1.32(2H, m), 1.52–1.61(2H, m), 1.65–1.71 Example 26 using 4- (M+H) (2H, m), 1.88–1.95(2H, m), 2.32–2.46(3H, m), 2.60–2.68(2H, m), Fluorobenzylisocyanate 2.70–2.76(2H, m), 4.01(2H, d), 4.19(2H, d), 4.38–4.44(1H, m), 6.97(1H, dd), 7.05(1H, t), 7.11(2H, t), 7.24–7.29(3H, m), 7.49(1H, d) MS = Mass Spectrum has been obtained using either APCI+ or ES+ or ES−

The preparations of certain inter-mediates are now presented.

Method A 1-(3-Methoxy-4-nitro-benzoyl)-piperidin-4-one

CDI (9 g) added to a solution of 3-methoxy-4-nitrobenzoic acid (10 g) stirring in THF (200 ml) at RT. After 1 hour, 4-piperidone hydrochloride (6.9 g) and triethylamine (7.8 ml) were added and the mixture stirred overnight. The mixture was diluted with ethyl acetate, washed with 2N HCl (100 ml) then saturated NaHCO₃ solution (200 ml) then saturated brine (200 ml). The organic layer was dried (MgSO₄) and evaporated to leave a residue which was purified by column chromatography (silica, mixtures of MeOH in dichloromethane) to give the product as a yellow solid (8.5 g; MS: APCI⁺(M+H) 279).

Method B 1-(3-Methanesulfonyl-benzoyl)-piperidin-4-one

PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonyl benzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base (25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture was stirred overnight then washed with saturated NaHCO₃ solution (200 ml) and then with saturated brine (200 ml). The organic layer was evaporated and the resulting residue purified by column chromatography (silica, 1:1 ethyl acetate:dichloromethane) to give the product as a thick oil (9.6 g; MS: APCI⁺(M+H) 282).

Method C 1-(Benzo[1,2,3]thiadiazole-5-carbonyl)-piperidin-4-one

CDI (4.5 g) added to a solution of the benzo[1,2,3]thiadiazole-5-carboxylic acid (5 g) stirring in THF (100 ml) at RT. After 1 hour 4-piperidone hydrochloride (3.7 g) and triethylamine (4.3 ml) were added and the mixture stirred overnight. The resulting mixture was diluted with ethyl acetate, washed with 2M HCl (100 ml), saturated NaHCO₃ solution (200 ml) and then with saturated brine (200 ml). The organic layer was dried (MgSO₄) and evaporated to leave a residue which was purified by column chromatography (silica, eluting with mixtures of ethyl acetate in dichloromethane) to give the product as a yellow oil (2.1 g; MS: APCI⁺(M+H)262).

Method D [1,4′]Bipiperidinyl-4-ol

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and 4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200 ml) with acetic acid (4 ml) at RT for 30 minutes. Sodium triacetoxyborohydride (23 g) was then added and the mixture stirred at RT overnight. The mixture was evaporated to dryness and the residue taken into water, extracted with diethyl ether (3×200 ml), the aqueous was basified to pH 9–10 and extracted with dichloromethane (3×200 ml). The dichloromethane extracts were combined, dried (MgSO₄) and evaporated to leave an oil (19 g; same compound as Example 9 step 1). The oil was dissolved in methanol (300 ml) and treated with concentrated hydrochloric acid (5 ml). The mixture was stirred overnight and then evaporated to dryness to leave the title compound as the hydrochloride salt (15 g).

¹H NMR (400 MHz, DMSO-D6) δ 1.6–2.4 (m, 9H), 2.8–3.5 (m, 8H), 3.62 (m, 1H), 3.95 (s, 1H), 9.29 and 9.059 (bs, 2H), 10.9 and 11.09 (bs, 1H).

Method E (4-Hydroxy-[1,4′]bipiperidinyl-1′-yl)-(3-methanesulfonyl-phenyl)-methanone

PyBrOP™ (25.3 g) was added to a stirred solution of 3-methanesulphonyl benzoic acid (10 g), [1,4′]bipiperidinyl-4-ol dihydrochloride (13 g, see Method D) and Hunig's base (34 ml) in dichloromethane (500 ml). The resulting mixture was stirred at RT overnight, then washed with saturated NaHCO₃ solution (300 ml) followed by saturated brine (300 ml). The organic layer was dried (MgSO₄) and evaporated to leave an oily residue. Column chromatography (silica, 20% methanol in DCM) gave the product as a white solid (16 g; MS: APCI⁺(M+H) 367).

Method F 4-(3-Chloro-4-fluoro-phenoxy)-piperidine

DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g), 3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture was stirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixture stirred at RT overnight. The mixture was then evaporated to dryness and triethylamine (5 ml) was added. The mixture was evaporated and the residue was dissolved in methanol (110 ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge available from International Sorbent Technology Isolute® Flash SCX-2) and eluted: first with methanol then with 10% NH₃ in methanol. The basic fractions were combined and evaporated to give the product as an oil (0.6 g).

¹H NMR (299.946 MHz, DMSO-D6) δ 1.34–1.46 (2H, m), 1.83–1.91 (2H, m), 2.53–2.59 (2H, m), 2.87–2.96 (2H, m), 3.22–3.39 (1H, m), 4.39 (1H, septet), 6.92–6.98 (1H, m), 7.17–7.20 (1H, m), 7.30 (1H, t).

The following intermediates were prepared in similar manner to Method F:

MS: (M + H) 4-(4-chloro-2-methyl-phenoxy)-piperidine 226 4-(4-chloro-3-fluoro-phenoxy)-piperidine 230 4-(4-chloro-2-methoxy-phenoxy)-piperidine 242 4-(4-fluoro-2-methoxy-phenoxy)-piperidine 226 4-(4-methoxy-phenoxy)-piperidine 208 4-p-tolyloxy-piperidine 192 4-(4-chloro-3-methyl-phenoxy)-piperidine 226 4-(4-chloro-phenoxy)-piperidine 212 4-(4-fluoro-phenoxy)-piperidine 196 4-(2,4-dichloro-phenoxy)-piperidine 246 4-(2-chloro-4-fluoro-phenoxy)-piperidine 230 4-(2,4-difluoro-phenoxy)-piperidine 214 4-(4-chloro-2-fluoro-phenoxy)-piperidine 230 4-(4-fluoro-2-methyl-phenoxy)-piperidine 210 4-(4-chloro-2,6-dimethyl-phenoxy)-piperidine 240 4-(2,3-dichloro-phenoxy)-piperidine 246 4-(2,5-dichloro-phenoxy)-piperidine 246 4-(2-chloro-4-methyl-phenoxy)-piperidine 226 4-(2-chloro-5-methyl-phenoxy)-piperidine 226 1-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-ethanone 234 4-(2-chloro-6-methyl-phenoxy)-piperidine 226 4-[2-(piperidin-4-yloxy)-phenyl]-morpholine 263 4-(4-chloro-2-ethyl-phenoxy)-piperidine 240 7-(piperidin-4-yloxy)-quinoline 229 4-(2-tert-butyl-phenoxy)-piperidine 234 4-(indan-5-yloxy)-piperidine 218 4-(4-chloro-2-cyclohexyl-phenoxy)-piperidine 294 5-chloro-2-(piperidin-4-yloxy)-benzamide 255 4-(4-chloro-2-isoxazol-5-yl-phenoxy)-piperidine 279 4-(5-chloro-2-methyl-phenoxy)-piperidine 226 4-phenoxy-piperidine 178 4-(2,4-dichloro-6-methyl-phenoxy)-piperidine 260 4-(3-chloro-4-methyl-phenoxy)-piperidine 226 5-chloro-2-(piperidin-4-yloxy)-benzonitrile 237 4-(2,4-dichloro-3-methyl-phenoxy)-piperidine 260 4-(2-ethyl-4-fluoro-phenoxy)-piperidine 224 4-(4-methanesulfonyl-phenoxy)-piperidine 297

Method G 4-Amino-3-ethoxy-benzoic acid

Potassium hydroxide (0.278 g) was added to a solution of 3-fluoro-4-nitrobenzoic acid (0.4 g) in ethanol (7 ml) and the reaction treated with microwaves (300W, 100° C.) for 55 minutes. The reaction mixture was acidified using 2N HCl and extracted with ethyl acetate. The extracts were combined, washed with water, dried (MgSO₄) and evaporated to give 3-ethoxy-4-nitro-benzoic acid (0.325 g).

3-Ethoxy-4-nitrobenzoic acid (0.31 g) was treated with 5% palladium on charcoal under an atmosphere of hydrogen (1 bar) for 3 hours. The reaction mixture was filtered and the filtrate was evaporated to leave the product as a beige solid (0.245 g; MS: ES⁻ (M−H) 180).

Method H 3,4-bis-Methanesulfonyl-benzoic acid

To 3-fluoro-4-nitro-benzoic acid tert-butyl ester (0.5 g) in DMSO was added NaSO₂Me. The reaction mixture was heated to 100° C. for 24 hours. A mixture of water, diethyl ether and ethyl acetate (1:1:1) was added and the resulting mixture was extracted with diethyl ether/ethyl acetate (1:1). The organic extracts were combined, dried with MgSO₄ and concentrated to leave a residue which was purified by chromatography (using 80% ethyl acetate/20% hexane) to give 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (366 mg). ¹H NMR (399.98 MHz, DMSO-D6) 1.59 (9H, s), 3.50 (3H, s) 3.52 (3H, s), 8.37–8.65 (3H, m).

To 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (0.366 g) in dichloromethane was added trifluoroacetic acid and the reaction mixture was stirred for 3 hours. The mixture was evaporated and trituration of the residue with diethyl ether gave the title compound (0.29 g; MS: APCI⁺(M+H) 279).

Method I 4-Carbamoyl-5-methanesulfonyl-thiophene-2-carboxylic acid

To 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid methyl ester (0.5 g) in THF/H₂O (3:1; 16 ml) was added LiOH (0.102 g). Hydrochloric acid (2M) was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined and the solvent evaporated to leave a mixture of 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid and the title compound. This mixture was used without further purification. ¹H NMR (299.944 MHz, DMSO-D6) δ 3.62 (3H, s), 7.99 (1H, s).

Method J 3-(2-Methyl-propane-1-sulfonyl)-benzoic acid

To a suspension of 3-sulfo-benzoic acid (1 g) and potassium carbonate (1.2 g) in dimethylacetamide (10 ml) was added iso-butyl iodide (0.65 ml). The mixture was heated by microwaves (600W) at 150° C. for 15 minutes. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the aqueous layer was separated, acidified to pH 1 with HCl (2N) and extracted with ethyl acetate (100 ml). The extract was evaporated to leave a residue which was purified by flash chromatography (Biotage 12S eluting with ethyl acetate:hexane:acetic acid, 29:70:1) to give the title product as a white solid (0.34 g).

¹H NMR: (399.98 MHz, DMSO-D6) δ 0.98 (6H, d), 2.03 (1H, septet), 3.29 (2H, d), 7.81 (1H, t), 8.16 (1H, ddd), 8.27 (1H, dt), 8.38 (1H, t).

3-Cyclopropylmethanesulfonyl-benzoic acid was prepared in a similar manner to that described in Method J. MS: (M−H) 239; ¹H NMR: (DMSO-d6) δ 0.06–0.10 (2H, m), 0.40–0.45 (2H, m), 0.82–0.89 (1H, m), 3.34 (2H, d), 7.80 (1H, t), 8.14 (1H, d), 8.28 (1H, d), 8.39 (1H, s).

Method K 3-(2-Methoxy-ethoxy)-benzoic acid methyl ester

To a solution of methyl 3-hydroxybenzoate (5.7 g) and 2-bromoethylmethyl ether (5.2 g) in dimethylformamide (100 ml) was added caesium carbonate (24.3 g). The reaction mixture was stirred for 12 hours. The mixture was then patitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was separated, dried (MgSO₄) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (Biotage 12M, eluting iso-hexane then MeOH:dichloromethane 2:98) to give the product as a colourless oil (5.3 g).

¹H NMR: (CDCl₃) δ 3.44 (3H, s), 3.75 (2H, t), 3.89 (3H, s), 4.15 (2H, t), 7.13 (1H, ddd), 7.32 (1H, t), 7.57 (1H, dd), 7.62 (1H, dt).

3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester can be prepared in a similar manner to that described in Method K: ¹H NMR: (299.944 MHz CDCl₃) 1.49 (9H, s), 3.91 (3H, s), 4.56 (2H, s), 7.13–7.68 (4H, m).

Method L 3-(2-Methoxy-ethoxy)-benzoic acid

To a suspention of 3-(2-methoxy-ethoxy)-benzoic acid methyl ester (5.3 g) in tetrahydrofuran (200 ml) was added lithium hydroxide monohydrate (5.3 g) followed by water until an homogeneous solution was obtained. The reaction mixture was stirred for 12 hours, acidified and partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was separated, dried (MgSO₄) and the solvent removed under reduced pressure to yield a colourless solid (3.6 g).

¹H NMR: (DMSO-D6) δ 3.31 (3H, s), 3.67 (2H, t), 4.14 (2H, t), 7.20 (1H, ddd), 7.41 (1H, t), 7.44 (1H, dd), 7.53 (1H, dt)

3-(2-tert-Butoxycarbonylamino-ethoxy)-benzoic acid can be prepared in a similar manner to that described in Method L.

3-tert-Butoxycarbonylmethoxy-benzoic acid can be prepared in a similar manner to that described in Method L: ¹H NMR (299.944 MHz, DMSO-D6) δ 2.51 (9H, s), 4.74 (2H, s), 7.18 (1H, dq), 7.38 (1H, m), 7.41 (1H, m), 7.55 (1H, dt), 13.03 (1H, s).

Method M 4-(2-Carboxy-2-phenyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester

Piperazine-1-carboxylic acid tert-butyl ester (17.43 g) and 2-phenylacrylic acid (18 g) in iso-propanol (500 ml) was heated at reflux for four days. The resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give the title compound as a white solid (17 g; MS: APCI⁺(M+H) 335).

Method N 5-Methanesulfonyl-1H-indole-2-carboxylic acid

To a solution of the 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester (0.49 g) in THF (12 mL) and water (4 ml) was added LiOH (0.098 g). The reaction mixture was left to stir for 2 hours. Acetic acid was added and the product extracted with dichloromethane. The organic extracts were combined, dried with magnesium sulfate, filtered and the filtrate evaporated to give the title compound as a solid (0.110 g).

¹H NMR (299.946 MHz, DMSO-D6) δ 3.18 (3H, s), 7.32–7.33 (1H, m), 7.61–7.64 (1H, m), 7.73–7.77 (1H, m), 8.30–8.31 (1H, m).

Method O

5-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid was prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (see Example 25) using the commercially available 5-methyl-1,8a-dihydro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. 6-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid and 6-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester were prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid and its ester above.

Method P Preparation of 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l⁶-benzo[1,4]thiazine-6-carboxylic acid

Step 1: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l⁶-benzo[1,4]thiazine-6-carboxylic acid methyl ester

To a solution of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g) in dichloromethane (25 ml) was added 32% peracetic acid dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 48 hours and then diluted with dichloromethane. The organic phase was washed once with water, twice with aqueous sodium sulfite solution, and once with saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated to give the sub-title compound as a solid (1.012 g).

¹H NMR (399.978 MHz, CDCl₃) δ 3.58 (3H, s), 4.00 (3H, s), 4.27 (2H, s), 7.96–7.99 (2H, m), 8.04–8.06 (1H, m).

Step 2: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l⁶-benzo[1,4]thiazine-6-carboxylic acid

To a solution of 4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g, from step 1) in MeOH (7 ml) was added dropwise a solution of sodium hydroxide (0.6 g) in water (5 ml). The reaction mixture was stirred at room temperature for 1 hour, diluted with water, cooled in an ice/water bath. Slow acidification with HCl (1N) to pH 2 yielded a precipitate which was isolated by filtration to give the title compound (0.595 g) as a solid.

¹H NMR (399.978 MHz, DMSO-D6) δ 3.49 (3H, s), 4.91 (2H, s), 7.90–8.03 (3H, m).

Method Q Preparation of 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl

Step a: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester

To a solution of 4-(4-methanesulfonyl-phenoxy)-piperidine (0.7 g) dissolved in THF (5 ml) and 1,2-dichloroethane (10 ml) with 1-Boc-4-piperidone (0.71 g) was added NaBH(OAc)₃ (0.926 g) and acetic acid (0.18 g). After 16 hours at RT aqueous NaOH (1M) solution and dichloromethane were added and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, dried with magnesium sulfate and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol 90:10) to give the sub-title product (1.1 g; MS: APCI⁺(M+H) 439).

Step b: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl

The product of step a was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (5 ml) was added. After 16 hours at room temperature the solution was evaporated to leave the title compound as a TFA salt. The free base (0.7 g; oil; MS: APCI⁺(M+H) 339) was liberated by addition of aqueous NaOH (1M) and extraction with dichloromethane followed by evaporation of the solvent.

3-Methanesulfonyl-5-nitro-benzoic acid and 3-cyano-5-methanesulfonyl-benzoic acid can be prepared according to a method described in EP-A1-556674.

2-amino-5-MeSO₂-benzoic acid can be prepared according to a method described in J. Org. Chem. (1953) 18 1380.

3-Ethanesulfonyl-benzoic acid can be prepared according to a method described in J. Chem. Soc. 1946, 763.

3-Methylsulfamoyl-benzoic acid and 3-dimethylsulfamoyl-benzoic acid can be prepared according to a method described in DE2133038. 3-Methylsulfamoyl-benzoic acid ¹H NMR: (399.98 MHz, DMSO-D6) δ 7.42 (3H, d), 7.63 (1H, q), 7.76 (1H, t), 8.01 (1H, m), 8.18 (1H, dt)), 8.31 (1H, t), 13.48 (1H, s).

Other intermediates can be prepared by literature methods, by adaptation of literature methods or are available commercially. For example:

-   (2-methyl-4-nitro-2H-pyrazol-3-yl)methanecarboxylic acid,     2-{1-[sulfonyl chloride]-ethyl}-isoindole-1,3-dione and     (1,3-dimethyl-3,7-dihydro-purine-2,6-dion-8-yl)methanecarboxylic     acid are available from Salor (Aldrich Chemical Company Inc 1001     West Saint Paul Avenue Milwaukee, Wis. 53233 USA); -   [4-amino-5-(iso-propyl-sulfonyl)-thiophen-3-yl]carboxylic acid,     [3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-isoxazol-4-yl]carboxylic     acid, 3-cyano-4-(pyrrol-1-yl)-thiophen-5-yl)carboxylic acid,     4-isopropylsulfanyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic     acid and     1-cyclopropyl-5-methoxy-2-methyl-2,3-dihydro-1H-indole-3-carboxylic     acid, (5-(isoxazol-3-yl)-thiophen-2-yl)sulfonyl chloride,     4-bromo-1-methyl-1H-pyrazol-3-ylmethanal,     4-chloro-1H-pyrazol-3-ylmethanal and     1-(4-chloro-benzyl)-1H-pyrazol-3-ylmethanal are available from     Maybridge Chemical Company Ltd.; Trevillett, Tintagel, Cornwall PL34     0HW, UK; -   (5-methanesulfonyl-1H-indol-2-yl)carboxylic acid is available by     hydrolysis of an ester available from Maybridge Chemical Company     Ltd., details above; -   (4-chloro-5-methyl-3-nitro-pyrazol-1-yl)methanecarboxylic acid,     (5-methyl-3,4-dinitro-pyrazol-1-yl)methanecarboxylic acid and     (2,4-dinitro-imidazol-1-yl)methanecarboxylic acid are available from     ASINEX Ltd., 6 Schuklinskaya ulitsa, Moscow 123182, Russia; -   (6-(imidazol-1-yl)-pyridin-3-yl)carboxylic acid and     2-methyl-2-([1,2,4]triazol-1-yl)-propanoic acid are available from     Bionet Research Ltd, 3 Highfield Industrial Estate, Camelford,     Cornwall PL32 9QZ, UK; and, -   (2-methyl-[1,8]naphthyridin-3-yl)carboxylic acid,     (2-methyl-[1,6]naphthyridin-3-yl)carboxylic acid and     (5-trifluoromethyl-thieno[3,2-b]pyridin-6-yl)-methanecarboxylic acid     are available from Peakdale Fine Chemicals Ltd., 7 Brookfield     Industrial Estate, Glossop, Derbyshire, SK13 6LQ, UK.

EXAMPLE 28 Pharmacological Analysis: Calcium Flux [Ca²⁺]_(i) Assay

Human Eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105–110). The cells were resuspended (5×10⁶ ml⁻¹) and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM, glucose 5.5 mM, Na₂CO₃ 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 2.5×10⁶ ml⁻¹. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 μM fibronectin for two hours) at 25 μl/well. The plate was centrifuged at 200 g for 5 min and the cells were washed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to a final concentration of 0.1% (v/v) DMSO. Assays were initiated by the addition of an A₅₀ concentration of eotaxin and the transient increase in fluo-3 fluorescence (1_(Ex)=490 nm and 1_(Em)=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).

Human Eosinophil Chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105–110). The cells were resuspended at 10×10⁶ ml⁻¹ in RPMI containing 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μl of either vehicle or compound (100× required final concentration in 10% DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loaded by adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate. The filter was then placed over the wells and 25 μl of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C. in a humidified incubator with a 95% air/5% CO₂ atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300×g for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysed by the addition of 28 μl of PBS containing 0.5% Triton ×100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.

Compounds of the Examples were found to be antagonists of the eotaxin mediated human eosinophil chemotaxis.

EXAMPLE 29

Guinea-pig Isolated Trachea

(See for example, Harrison, R. W. S., Carswell, H. & Young, J. M. (1984) European J. Pharmacol., 106, 405–409.)

Male albino Dunkin-Hartley guinea-pigs (250 g) were killed by cervical dislocation and the whole trachea removed. After clearing the adherent connective tissue, the trachea was cut into six ring segments each three cartilage bands wide and then suspended in 20 ml organ baths containing Krebs-Henseleit solution of the following composition (mM): NaCl 117.6, NaH₂PO₄ 0.9, NaHCO₃ 25.0, MgSO₄ 1.2, KCl 5.4, CaCl₂ 2.6 and glucose 11.1. The buffer was maintained at 37° C. and gassed with 5% CO₂ in oxygen. Indomethacin (2.8 μM) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo-oxygenase products. The tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders.

Experimental Protocols

At the beginning of each experiment a force of 1 g was applied to the tissues and this was reinstated over a 60 minute equilibration period until a steady resting tone was achieved. Subsequently, a cumulative histamine concentration effect (E/[A]) curve was constructed at 0.5 log₁₀ unit increments, in each tissue. The tissues were then washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added. Following an incubation period of 60 minutes a second E/[A] curve was performed to histamine.

Contraction responses were recorded as a percentage of the first curve maximum.

Data Analysis

Experimental E/[A] curve data were analysed for the purposes of estimating the potencies (p[A₅₀] values) of histamine in the absence and presence of the test compound. Affinity (pA₂) values of test compounds were subsequently calculated using the following equation: log(r−1)=log[B]+pA ₂ where r=[A]₅₀ in presence of test compound/[A]₅₀ in absence of antagonist and [B] is the concentration of test compound. Compounds of the Examples were found to be H1 antagonists. 

1. A compound of formula (XIIIa):

wherein: L² is hydrogen, tert-butoxycarbonyl or benzyl; t is 1; m and p are 1; X is O; R¹ is phenyl optionally substituted with one or more of halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy.
 2. A compound as claimed in claim 1 wherein R¹ is phenyl substituted with one or more of fluorine, chlorine, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 3. A compound as claimed in claim 1 wherein R¹ is phenyl substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 4. A compound as claimed in claim 1 wherein R¹ is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
 5. A compound of formula (XIII):

wherein: t is 1; m and p are 1; X is O; R¹ is phenyl optionally substituted with one or more of halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy.
 6. A compound as claimed in claim 5 wherein R¹ is phenyl substituted with one or more of fluorine, chlorine, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 7. A compound as claimed in claim 5 wherein R¹ is phenyl substituted by haolgen, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 8. A compound as claimed in claim 5 wherein R¹ is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
 9. A compound of formula (XIV):

wherein: L* is BOC or a benzyl group; t is 1; m and p are 1; X is O; R¹ is phenyl optionally substituted with one or more of halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy.
 10. A compound as claimed in claim 9 wherein R¹ is phenyl substituted with one or more of fluorine, chlorine, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 11. A compound as claimed in claim 9 wherein R¹ is phenyl substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 12. A compound as claimed in claim 9 wherein R¹ is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
 13. A compound as claimed in claim 1 wherein R¹ is 3,4-dichlorophenyl or 3,4-difluorophenyl.
 14. A compound as claimed in claim 1 wherein R¹ is 3,4-dichlorophenyl.
 15. A compound as claimed in claim 5 wherein R¹ is 3,4-dichlorophenyl or 3,4-difluorophenyl.
 16. A compound as claimed in claim 5 wherein R¹ is 3,4-dichlorophenyl.
 17. A compound as claimed in claim 9 wherein R¹ is 3,4-dichlorophenyl or 3,4-difluorophenyl.
 18. A compound as claimed in claim 9 wherein R¹ is 3,4-dichlorophenyl. 